The present invention relates to an amine compound having an excellent effect of inhibiting production and/or secretion of amyloid-xcex2 protein, a production and use thereof. Especially, it is effective for preventing and/or treating, for example, neurodegenerative diseases, amyloid angiopathy, neurological disorders caused by cerebrovascular disorders, and so forth.
Alzheimer""s disease is a neurodegenerative disease, which is characterized by the degeneration and loss of neuronal cells accompanied by the formation of senile plaques and neurofibrillary tangles. Senile plaque that is the most characteristic in Alzheimer""s disease consist of essentially amyloid-xcex2 protein (hereinafter referred to as Axcex2) [see Biochem. Biophys. Res. Commun., 122, 1311 (1984)] and other intracerebral components. It is known that Axcex2 comprised of 40 or 42 amino acids (hereinafter referred to as Axcex21-40 and Axcex21-42, respectively) is toxic to neurons and induces neurofibrillary changes.
Some patients with familial Alzheimer""s disease are known to have APP (amyloid precursor protein) gene mutation, and it is well known that the cells transfected with such mutated gene produce and secrete an increased amount of Axcex2 [for example, see Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994), etc.].
Based on the information, medicines which inhibit production and/or secretion are useful for preventing and/or treating diseases caused by Axcex2 (e.g., Alzheimer""s disease, Down""s syndrome, etc).
Alternatively, secreted form of amyloid precursor protein (sAPP) is reported to have neurotrophic factor like property (Neuron, 10, 243-254,1993). As neurotrophic factor like property, 1) survival and preserving effect to the neuronal cell; 2) stimulating the synapse formation; 3) protection of neuronal cell death; and 4) long term potentiation in hippocampus are given as examples. By the above-mentioned property, drugs which stimulate the sAPP secretion are also useful in preventing and treating 1) neurodegenerative diseases such as dementia (e.g., senile dementia, amnesia, etc.), Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus, Huntington""s disease, multiple sclerosis, etc., 2) neurological disorders involved in cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, and so forth.
EP-A-652009 discloses peptide derivatives which is a protease inhibitor exhibiting an Axcex2 production inhibiting effect in in vitro experiments using cell lines.
On the other hand, the following bicyclic amine compounds are known.
1) JP-A-2-96552 (U.S. Pat. No. 5,137,901) discloses a compound of the formula: 
wherein Y represents a straight-chain or branched, substituted or unsubstituted alkylene chain having up to 6 carbon atoms; Z represents a group of the formula: xe2x80x94NR2R3, xe2x80x94OR4, or the like; R2 and R3 are identical or different and represent hydrogen, alkyl, alkenyl or cycloalkyl, or represent aryl which may be substituted by halogen, etc.; R4 represents hydrogen, alkyl, alkenyl, or the like; R1 represents hydrogen, alkyl, aralkyl, heteroarylalkyl or a group of the formula: xe2x80x94(Y1xe2x80x94Z1) in which Y1 and Z1 are identical or different and have the same meanings as Y and Z; A and D each represents a group of the formula:
xe2x80x94CH2, O, S or NR13,
or the moiety of xe2x80x94CH or N of a double bond Cxe2x95x90C or Cxe2x95x90NH, with the proviso that either only A or only D represents oxygen, sulfur or Nxe2x80x94R13; R13 represents hydrogen, alkyl, alkoxy, acyl, alkoxycarbonyl or alkylsulfonyl; B represents a group of the formula:
xe2x80x94CH2
or 
or the moiety of xe2x80x94CH or N of a double bond Cxe2x95x90C or Cxe2x95x90N; C represents a group of the formula: 
or the moiety of C of a double bond Cxe2x95x90C or Cxe2x95x90N; E and F are identical or different and each represents hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy or a group of the formula:
xe2x80x94CONR2R3
in which R2 and R3 have the same meanings as above, or E and F together form a substituted or unsubstituted carbocycle having 6 carbon atoms, which is agonist, partial agonist and antagonist on the serotonin receptors and is suitable for the treatment of central nervous system disorders, etc.
2) JP-A-63-77842 discloses a compound of the formula: 
wherein n represents 1 or 2; A represents a carbonyl while R7 is hydrogen, or A represents a group of the formula:
xe2x80x94CHR8xe2x80x94
wherein R8 represents hydrogen, alkanoyloxy or alkoxycarbonyl, while R7 is hydrogen or R7 and R8 together form another bond; E represents a straight-chain alkylene which has 3 or 4 carbon atoms and may be substituted by an alkyl; G represents a straight-chain alkylene which has 2 to 5 carbon atoms and may be substituted by an alkyl; R1 represents hydrogen, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy; R2 represents hydrogen, halogen atoms, hydroxy, alkoxy, phenylalkoxy or alkyl; or R1 and R2 together form an alkylenedioxy having 1 or 2 carbon atoms; R3 represents hydrogen, alkenyl or alkyl having 3 to 5 carbon atoms; R4 represents hydrogen, halogen atoms, alkyl, or the like; R5 represents hydrogen, halogen atoms, alkyl, or the like; and R6 represents hydrogen, halogen atoms, alkyl, or the like, which is suitable for the treatment of sinus tachycardia and also for the prevention and treatment of ischemic heart disease because of its pharmacological action, decrease in the heart rate and oxygen demand of the heart.
3) WO 92/15558 discloses a compound of the formula: 
wherein n represents an integer of 1 to 4, which is an intermediate of a compound having a thromboxane A2 antagonistic effect.
4) WO 95/32967 discloses amide derivatives of the formula: 
wherein A is CONR where R is hydrogen or C1-6 alkyl; Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R1 is hydrogen, halogen, etc.; R2 and R3 are independently hydrogen, halogen, etc.; R4 and R5 are independently hydrogen or C1-6 alkyl; R6 is halogen, hydroxy, etc.; R7 and R8 are independently hydrogen, C1-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached from an optionally substituted 5 to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; m is 0 to 4; and n is 0, 1 or 2, which has 5HT1D receptor antagonist activity and is useful for the treatment of various CNS disorders.
5) EP-A-754455 discloses a pharmaceutical compositions for the therapeutic application as neuroprotectors in Parkinson""s and Alzheimer""s diseases containing a compound of the formula: 
wherein X is H, halogen, alkoxy, alkyl, alkylthio, aryl, aryloxy; R is H, CH3 or other aliphatic, alicyclic or aryl radicals; Rxe2x80x2 is H, CH3 or other aliphatic or alicyclic C1-C3 radicals, or an aryl or arylalkyl, or a radical the same as those indicated for Rxe2x80x3; and Rxe2x80x3 is H, CH3 or other aliphatic or alicyclic C1-C3 radicals, or an aryl or arylalkyl, or an acetylene or allene group, being potent selective monoamine oxydase B inhibitors.
The conventional Axcex2 production inhibitors for the treatment of Alzheimer""s disease are problematic in their oral absorbability, stability, etc. and are therefore unsatisfactory as medicines. It is desired to develop a compound which is different from the known compounds mentioned above in its chemical structure and which have an excellent inhibitory effect on Axcex2 production and/or secretion and is therefore satisfactorily used in medicines.
We, the present inventors have studied various compounds having an inhibitory effect on Axcex2 production and/or secretion and, as a result, have succeeded in, for the first time, the production of novel a compound of the formula: 
wherein Ar represents an aromatic ring assembly group which may be substituted or a fused aromatic group which may be substituted;
X represents (i) a bond, (ii) xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, (iii) a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group, each of which may be substituted by 1 to 3 substituents selected from the group consisting of oxo and C1-6 alkyl, (iv) xe2x80x94COxe2x80x94Oxe2x80x94 or (v) a group of the formula:
xe2x80x94(CH2)pxe2x80x94X1xe2x80x94, xe2x80x94(CH2)p-X1xe2x80x94(CH2)q-, xe2x80x94(CH2)r-COxe2x80x94X1xe2x80x94, xe2x80x94SO2xe2x80x94NR8xe2x80x94
or
xe2x80x94(CH2)r-SO2xe2x80x94NR8xe2x80x94
xe2x80x83wherein X1 represents O (oxygen atom) or NR8, R8 represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl, p represents an integer of 0 to 5, q represents an integer of 1 to 5, p+q is an integer of 1 to 5, and r represents an integer of 1 to 4;
Y represents a divalent C1-6 aliphatic hydrocarbon group which may contain an oxygen atom or a sulfur atom and may be substituted;
R1 and R2 each represents a hydrogen atom or a lower alkyl which may be substituted, or
R1 and R2 form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted;
Ring A represents a benzene ring which may be further substituted apart from the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above; and
Ring B represents a 4- to 8-membered ring which may be further substituted apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
xe2x80x83wherein each symbol is as defined above;
provided that, when the fused ring to be formed by Ring A and Ring B is an indole ring, the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above is substituted on 4-, 6- or 7-position of the indole ring, or a salt thereof [hereinafter sometimes referred to as compound (I)], which is characterized by the chemical structure in that the benzene ring A of the skeleton of the formula: 
xe2x80x83wherein the symbols have the same meanings as above, is substituted by the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein the symbols have the same meanings as above. We have found for the first time that compound (I), being based on its specific chemical structure, has an unexpected, excellent inhibitory effect on Axcex2 production and/or secretion, that a compound of the formula: 
xe2x80x83wherein Arxe2x80x2 represents an aromatic group which may be substituted, and the other symbols have the same meanings as above, or salt thereof [hereinafter sometimes referred to as compound (Ixe2x80x2)] also has an unexpected, excellent inhibitory effect on Axcex2 production and/or secretion, and that those compounds have low toxicity and are therefore satisfactory as medicines. Compound (I) is within the scope of compound (Ixe2x80x2). On the basis of these findings, the inventors have completed the present invention.
Specifically, the present invention relates to:
(1) a compound of the formula: 
wherein Ar represents an aromatic ring assembly group which may be substituted or a fused aromatic group which may be substituted;
X represents a chemical bond or a spacer of which the number of atoms constituting the principal chain is 1 to 6;
Y represents a divalent C1-6 aliphatic hydrocarbon group which may contain an oxygen atom or a sulfur atom and may be substituted;
R1 and R2 each represents a hydrogen atom or a lower alkyl which may be substituted, or
R1 and R2 form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted;
Ring A represents a benzene ring which may be further substituted apart from the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above; and
Ring B represents a 4- to 8-membered ring which may be further substituted apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
xe2x80x83wherein each symbol is as defined above;
provided that, when the fused ring to be formed by Ring A and Ring B is an indole ring, the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above is substituted on 4-, 6- or 7-position of the indole ring, or a salt thereof;
(2) compound (I), wherein
Ar is (i) an aromatic ring assembly group which is composed of two or three rings selected from the class consisting of a C6-14 aromatic hydrocarbon, a C6-14 quinone and a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which rings are directly bonded to each other via a single bond, and which assembly group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or
(ii) a fused bi- or tri-cyclic C10-14 aryl or 9- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy;
R8 is (a) a hydrogen atom,
(b) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl being optionally condensed with one benzene ring, C6-14 aryl or C7-19 aralkyl group which may be substituted by 1 to 5 substituents selected form the group consisting of (1) halogen atoms, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 alkyl, (6) optionally halogenated C3-6 cycloalkyl, (7) optionally halogenated C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C1-6 alkylamino, (12) di-C1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, (14) formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido or C1-6 alkylsulfonylamino, (15) C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino, (17) sulfo, (18) a phenyl or 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (19) an aromatic ring assembly group which is composed of two or three rings selected from the class consisting of a C6-14 aromatic hydrocarbon, a C6-14 quinone and a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, are directly bonded to each other via a single bond, and which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-11 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, and (20) a fused bi- or tri-cyclic C10-14 aryl or 9- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or
(c) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl;
Y is a C1-6 alkylene, a C2-6 alkenylene, a C2-6 alkynylene or a group of the formula:
xe2x80x94(CH2)m-Y1xe2x80x94(CH2)n-
xe2x80x83wherein xe2x80x94Y1xe2x80x94 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94,
m is an integer of 0 to 4,
n is an integer of 1 to 5, and
m+n is an integer of 1 to 5;
R1 and R2 each is a hydrogen atom or a C1-6 alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy, C6-10 aryloxy and C6-10 aryl or
R1 and R2 form, taken together with the adjacent nitrogen atom, a 3- to 8-membered nitrogen-containing heterocyclic ring having one nitrogen atom and optionally having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which ring may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen atoms, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 alkyl, (6) optionally halogenated C3-6 cycloalkyl, (7) optionally halogenated C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C1-6 alkylamino, (12) di-C1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, (14) formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido or C1-6 alkylsulfonylamino, (15) C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino, (17) sulfo, (18) a phenyl or 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (19) an aromatic ring assembly group which is composed of two or three rings selected from the class consisting of a C6-14 aromatic hydrocarbon, a C6-14 quinone and a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, are directly bonded to each other via a single bond, and which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (20) a fused bi- or tri-cyclic C10-14 aryl or 9- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (21) an oxo and (22) C7-19 aralkyl;
Ring A is a benzene ring which may be further substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, hydroxy and amino, apart from the group of the formula:
xe2x80x94Xxe2x80x94Ar
wherein each symbol is as defined above; and
Ring B is a 4- to 8-membered ring of the formula: 
xe2x80x83wherein - - - is a single bond or a double bond, and Z is (i) a bond, (ii) a C1-4 alkylene, (iii) a C2-4 alkenylene, (iv) xe2x80x94Oxe2x80x94CH2xe2x80x94, (v) xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 or (vi) a group of the formula:
xe2x80x94NR8axe2x80x94CH2xe2x80x94
or
xe2x80x94NR8axe2x80x94CH2xe2x80x94CH2xe2x80x94
xe2x80x83wherein R8a is (a) a hydrogen atom,
(b) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl being optionally condensed with one benzene ring, C6-14 aryl or C7-9 aralkyl group which may be substituted by 1 to 5 substituents selected form the group consisting of (1) halogen atoms, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 alkyl, (6) optionally halogenated C3-6 cycloalkyl, (7) optionally halogenated C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C1-6 alkylamino, (12) di-C1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, (14) formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido or C1-6 alkylsulfonylamino, (15) C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino, (17) sulfo, (18) a phenyl or 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (19) an aromatic ring assembly group which is composed of two or three rings selected from the class consisting of a C6-14 aromatic hydrocarbon, a C6-14 quinone and a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, are directly bonded to each other via a single bond, and which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, and (20) a fused bi- or tri-cyclic C10-14 aryl or 9- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or
(c) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, which ring may be further substituted by 1 to 3 substituents selected from the group consisting of oxo, C1-6 alkyl and hydroxy, apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
wherein each symbol is as defined above;
(3) compound (I), wherein Ar is an aromatic ring assembly group which may be substituted;
(4) a compound of the above (3), wherein the aromatic rings of the aromatic ring assembly group are two or three aromatic rings selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene, and benzofuran;
(5) a compound of the above (3), wherein the aromatic ring assembly group is 2-, 3- or 4-biphenylyl;
(6) compound (I), wherein Ar is a 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy;
(7) compound (I), wherein X is a divalent C1-6 aliphatic hydrocarbon group which may contain an oxygen atom;
(8) compound (I), wherein X is a C1-6 alkylene;
(9) compound (I), wherein X is a group of the formula:
xe2x80x94(CH2)p-X1xe2x80x94
wherein each symbol is as defined above;
(10) a compound of the above (9), wherein p is 1;
(11) a compound of the above (10), wherein X1 is O;
(12) a compound of the above (10), wherein X1 is NR8b wherein R8b is hydrogen or C1-6 alkyl-carbonyl;
(13) compound (I), wherein X1 is a group of the formula:
xe2x80x94SO2xe2x80x94NR8xe2x80x94
wherein each symbol is as defined above;
(14) a compound of the above (13), wherein R8 is hydrogen;
(15) compound (I), wherein Y is a divalent C1-6 aliphatic hydrocarbon group;
(16) compound (I), wherein Y is C1-6 alkylene;
(17) compound (I), wherein R1 and R2 each is C1-6 alkyl;
(18) compound (I), wherein Ring A is a benzene ring substituted by the group of the formula:
xe2x80x94Xxe2x80x94Ar
wherein each symbol is as defined above;
(19) compound (I), wherein Ring B is a 4- to 8-membered ring of the formula: 
wherein Z is (i) a bond, (ii) a C1-4 alkylene, (iii) a C2-4 alkenylene, (iv) xe2x80x94Oxe2x80x94CH2xe2x80x94, (v) xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 or (vi) a group of the formula:
xe2x80x94NR8axe2x80x94CH2xe2x80x94
or
xe2x80x94NR8axe2x80x94CH2xe2x80x94CH2xe2x80x94
xe2x80x83wherein R8a is (a) a hydrogen atom,
(b) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl being optionally condensed with one benzene ring, C6-14 aryl or C7-19 aralkyl group which may be substituted by 1 to 5 substituents selected form the group consisting of (1) halogen atoms, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 alkyl, (6) optionally halogenated C3-6 cycloalkyl, (7) optionally halogenated C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C1-6 alkylamino, (12) di-C1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C3-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C3-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, (14) formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido or C1-6 alkylsulfonylamino, (15) C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino, (17) sulfo, (18) a phenyl or 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, (19) an aromatic ring assembly group which is composed of two or three rings selected from the class consisting of a C6-14 aromatic hydrocarbon, a C6-14 quinone and a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, are directly bonded to each other via a single bond, and which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, and (20) a fused bi- or tri-cyclic C10-14 aryl or 9- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or
(c) formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl, which ring may be further substituted by 1 to 3 substituents selected from the group consisting of oxo, C1-6 alkyl and hydroxy, apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
xe2x80x83wherein each symbol is as defined above;
(20) a compound of the above (19), wherein R8a is hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 ( aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl;
(21) compound (I), wherein Ring B is a 6-membered carbocyclic or heterocyclic ring substituted by a group of the formula:
xe2x80x94Yxe2x80x94NR1R2
wherein each symbol is as defined above;
(22) compound (I), wherein Ring B is a ring of the formula: 
wherein Za is C1-3 alkylene or a group of the formula:
xe2x80x94NR8cxe2x80x94CH2xe2x80x94
wherein R8c is hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl;
(23) a compound of the above (22), wherein Za is ethylene;
(24) compound (I), wherein the fused ring to be formed by Ring A and Ring B is a ring of the formula: 
(25) compound (I), wherein Ar is 2-, 3- or 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, formyl and C1-6 alkyl-carboxamido;
X is C1-3 alkylene which may contain an oxygen atom;
Y is C1-6 alkylene;
R1 and R2 each is C1-6 alkyl;
Ring A is a benzene ring substituted by the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above; and
Ring B is a 6-membered carbocyclic or heterocyclic ring substituted by the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
xe2x80x83wherein each symbol is as defined above;
(26) compound (I), which is a compound of the formula: 
wherein R0 is 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, formyl and C1-6 alkyl-carboxamido; and
R1a and R2a each is C1-6 alkyl, or a salt thereof;
(27) compound (I), which is a compound of the formula: 
wherein Ara is (i) 2, 3- or 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, amino, formyl and C1-6 alkyl-carboxamido, (ii) 4-(2-thienyl)phenyl or 4-(3-thienyl) phenyl, (iii) 4-(3-pyridyl)phenyl, (iv) 6-phenyl-3-pyridyl which may be substituted by a C1-6 alkoxy, (v) 5-phenyl-1,3,4-oxadiazol-2-yl, (vi) 4-(2-naphthyl) phenyl, (vii) 4-(2-benzofuranyl)phenyl, (viii) 1- or 2-naphthyl, (ix) 2-quinolyl, (x) 2-benzothiazolyl or (xi) 2-benzofuranyl;
Xxe2x80x2 is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94 or a group of the formula: xe2x80x94CH2xe2x80x94NR8xe2x80x2xe2x80x94wherein R8xe2x80x2 is hydrogen or C1-3 alkyl-carbonyl;
Yxe2x80x2 is C1-6 alkylene;
Zxe2x80x2 is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or a group of the formula: xe2x80x94NR8xe2x80x3xe2x80x94CH2xe2x80x94 wherein R8xe2x80x3 is hydrogen, C1-3 alkyl, C1-3 alkyl-carbonyl or C1-3 alkylsulfonyl; and
R1xe2x80x2 and R2xe2x80x2 each is C1-6 alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of di-C1-3 alkylamino, C1-3 alkoxy-carbonyl and phenyl, or
R1xe2x80x2 and R2xe2x80x2 form, taken together with the adjacent nitrogen atom, a pyrrolidin-1-yl, piperidino or piperazin-1-yl which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, C1-3 alkoxy-carbonyl, piperidino, phenyl and benzyl, or a salt thereof;
(28) compound (I) which is
6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino) methyltetralin,
2-(N,N-dimethylamino)methyl-6-(4xe2x80x2-methoxybiphenyl-4-yl) methoxytetralin,
(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino) ethyl]tetralin,
(+)-2-[2-(N,N-dimethylamino)ethyl]-6-(4xe2x80x2-methylbiphenyl-4-yl) methoxytetralin,
(+)-2-[2-(N,N-dimethylamino)ethyl]-6-(4xe2x80x2-methoxybiphenyl-4-yl) methoxytetralin,
(+)-6-(2xe2x80x2,4xe2x80x2-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
(+)-6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin, or
(+)-6-(3xe2x80x2,4xe2x80x2-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin, or a salt thereof;
(29) a process for producing of compound (I), which comprises;
i) subjecting a compound of the formula: 
xe2x80x83wherein Xa represents an oxygen atom, a sulfur atom which may be oxidized or a group of the formula:
NR8
xe2x80x83wherein R8 represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl; and the other symbols have the same meanings as above, or a salt thereof, to alkylation or acylation and optionally followed by aryl-coupling of the resultant compound;
ii) subjecting a compound of the formula: 
xe2x80x83wherein Ya represents a group to be formed by removing a methylene from Y; and the other symbols have the same meanings as above, or a salt thereof, to reduction; or
iii) subjecting a compound of the formula: 
xe2x80x83wherein L represents a leaving group; and the other symbols have the same meanings as above, to amination;
(30) an optical isomer of the compound of the formula: 
wherein R1b and R2b each represents methyl or ethyl, k represents 1 or 2, and * indicates the position of the asymmetric carbon, or a salt thereof;
(31) a pharmaceutical composition which comprises compound (I);
(32) a pharmaceutical composition of the above (31) which is an inhibitor for production and/or secretion of amyloid-xcex2 protein;
(33) a pharmaceutical composition of the above (31) which is for preventing and/or treating neurodegenerative diseases caused by amyloid-xcex2 protein;
(34) a pharmaceutical composition of the above (32), wherein the neurodegenerative disease caused by amyloid-xcex2 protein is Alzheimer""s disease;
(35) a method of inhibiting production and/or secretion of amyloid-xcex2 protein in mammal, which comprises administering to said mammal an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent;
(36) a use of compound (I) for manufacturing a pharmaceutical composition for inhibiting production and/or secretion of amyloid-xcex2 protein;
(37) an inhibitor for production and/or secretion of amyloid-xcex2 protein, which comprises compound (Ixe2x80x2);
(38) a method of inhibiting production and/or secretion of amyloid-xcex2 protein in mammal, which comprises administering to said mammal an effective amount of compound (Ixe2x80x2) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent;
(39) a use of compound (Ixe2x80x2) for manufacturing a pharmaceutical composition for inhibiting production and/or secretion of amyloid-xcex2 protein, and so forth.
In the above-mentioned formulae, the xe2x80x9caromatic ring assembly groupxe2x80x9d of the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d for Ar is meant to indicate a group which is derived, by removing an optional hydrogen atom from an assembled aromatic ring in which two or more, preferably two or three aromatic rings are directly joined to each other by single bond(s) and the number of such direct ring junctions is one less than the number of the aromatic rings involved. The xe2x80x9caromatic ringxe2x80x9d includes, for example, an aromatic hydrocarbon, an aromatic heterocyclic ring, etc.
The xe2x80x9caromatic hydrocarbonxe2x80x9d includes, for example, a C6-14 monocyclic or fused polycyclic (preferably, bi-or tri-cyclic) aromatic hydrocarbon compound (e.g., benzene, naphthalene, indene, anthracene, etc.) or a C6-14 quinone (e.g., p-benzoquinone, 1,4-naphthoquinone, indan-4,7-dione, etc.), etc.
The xe2x80x9caromatic heterocyclic ringxe2x80x9d includes, for example, 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic rings containing one or more (e.g., 1 to 4) hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, etc. Concretely mentioned is an aromatic heterocyclic ring, such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, phenoxathlin, pyrrole, imidazole, pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, phthalimide, etc.; and a ring as formed through condensation of the above ring, preferably monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., benzene ring, etc.), etc.
The assembly of those aromatic rings in which the rings are directly bonded to each other via a single bond includes, for example, those to be composed of two or three, preferably two aromatic rings selected from the group consisting of benzene ring, naphthalene ring and 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic ring. As specific examples of the assembly of such aromatic rings, mentioned are biphenyl, 2-phenylnaphthalene, p-terphenyl, o-terphenyl, m-terphenyl, 2-phenylpyridine, 3-phenylpyridine, 4-phenylpyridine, 2-phenylthiophene, 3-phenylthiophene, 2-phenylindole, 3-phenylindole, 5-phenyl-1,3,4-oxadiazole, etc. Among others, preferred is an assembly which is composed of two or three aromatic rings selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran.
Specific examples of the above xe2x80x9caromatic ring assembly groupxe2x80x9d are 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 4-(2-thienyl)phenyl, 4-(3-thienyl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 6-phenyl-3-pyridyl, 5-phenyl-1,3,4-oxadiazol-2-yl, 4-(2-naphthyl) phenyl, 4-(2-benzofuranyl)phenyl, etc. Of those, preferred are 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, etc. , especially preferred is 4-biphenylyl.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d includes, for example, halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, C6-10 aryloxy (e.g., phenyloxy, naphthyloxy, etc.), and so forth.
The xe2x80x9caromatic ring assembly groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the aromatic ring assembly group, and when the number of substituents is two or more, those substituents may be the same as or different from one another.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Thus, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. can be mentioned.
The above-mentioned xe2x80x9coptionally halogenated C3-6 cycloalkylxe2x80x9d includes, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Thus, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. can be mentioned.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d includes, for example, C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Thus, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. can be mentioned.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylthioxe2x80x9d includes, for example, C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Thus, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. can be mentioned.
The above-mentioned xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d includes, for example, morpholino, thiomorpholino, piperazin-1-yl, 4-substituted piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethyleneimin-1-yl, etc.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9c4-substituted piperazin-1-ylxe2x80x9d includes, for example, C1-6 alkyl, C6-14 aryl which may be substituted, C7-19 aralkyl which may be substituted, 5- to 10-membered aromatic heterocyclic group which may be substituted, acyl, and so forth.
The xe2x80x9cC6-14 arylxe2x80x9d of the xe2x80x9cC6-14 aryl which may be substitutedxe2x80x9d includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc. Preferred is phenyl.
The xe2x80x9cC7-19 aralkylxe2x80x9d of the xe2x80x9cC7-19 aralkyl which may be substitutedxe2x80x9d includes, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc. Preferred is benzyl, etc.
The xe2x80x9c5- to 10-membered aromatic heterocyclic groupxe2x80x9d of the xe2x80x9c5- to 10-membered aromatic heterocyclic group which may be substitutedxe2x80x9d includes, for example, 2-, 3- or 4-pyridyl, 1-, 2- or 3-indolyl, 2- or 3-thienyl, etc. Preferred is 2-, 3- or 4-pyridyl, etc.
The xe2x80x9csubstituentxe2x80x9d which those xe2x80x9cC6-14 aryl which may be substitutedxe2x80x9d, xe2x80x9cC7-19 aralkyl which may be substitutedxe2x80x9d and xe2x80x9c5- to 10-membered aromatic heterocyclic group which may be substitutedxe2x80x9d respectively may have, includes, for example, 1 to 5 substituents selected from the group consisting of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), carboxy, and so forth.
The xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d, xe2x80x9coptionally halogenated C3-6 cycloalkylxe2x80x9d, xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d and xe2x80x9coptionally halogenated C1-6 alkylthioxe2x80x9d include those described above, respectively.
The xe2x80x9cacylxe2x80x9d of (i) xe2x80x9cacylxe2x80x9d exemplified as substituents for the above xe2x80x9c4-substituted piperazin-1-ylxe2x80x9d, (ii) xe2x80x9cacylxe2x80x9d exemplified as substituents for the above xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d, (iii) the above xe2x80x9cacylaminoxe2x80x9d and (iv) the above xe2x80x9cacyloxyxe2x80x9d includes, for example, an acyl represented by the formula:
xe2x80x94(Cxe2x95x90O)xe2x80x94R3, xe2x80x94(Cxe2x95x90O)xe2x80x94OR3, xe2x80x94(Cxe2x95x90O)xe2x80x94NR3R4, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a or xe2x80x94SOxe2x80x94R3a
wherein R3 represents hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, R3a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, R4 represents hydrogen or C1-6 alkyl, or R3 and R4 may, together with the adjacent nitrogen atom, form a nitrogen-containing heterocyclic ring.
The xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R3 or R3a means a group formed by removing an optional hydrogen atom from a hydrocarbon compound, as exemplified by acyclic or cyclic hydrocarbon group such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl. Among them, the following C1-16 acyclic or cyclic hydrocarbon group is preferable:
a) C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
b) C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.),
c) C2-6 alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl, etc.),
d) C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), and the C3-6 cycloalkyl being optionally condensed with one benzene ring,
e) C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc.), preferably phenyl,
f) C7-19 aralkyl (e.g., benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.), preferably benzyl.
Among others, C1-6 alkyl, C6-14 aryl and C7-19 aralkyl are preferable.
Examples of the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d include halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, etc.), acyl, acylamino, acyloxy, 5- to 7-membered saturated cyclic amino, sulfo, aromatic group which may be substituted, and so forth.
The xe2x80x9chydrocarbon groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the hydrocarbon group and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
The above-mentioned xe2x80x9caromatic group which may be substitutedxe2x80x9d includes xe2x80x9caromatic group which may be substitutedxe2x80x9d for Arxe2x80x2 described hereinafter.
The xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d, xe2x80x9coptionally halogenated C3-6 cycloalkylxe2x80x9d, xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d, xe2x80x9coptionally halogenated C1-6 alkylthioxe2x80x9d, xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d, xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d and xe2x80x9cacyloxyxe2x80x9d mentioned above include, for example, those described in detail in the foregoing referring to the xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
Of these, preferred xe2x80x9cacylxe2x80x9d for xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d and xe2x80x9cacyloxyxe2x80x9d mentioned above is a group of the formula:
xe2x80x94(Cxe2x95x90O)xe2x80x94R3, xe2x80x94(Cxe2x95x90O)xe2x80x94OR3, xe2x80x94(Cxe2x95x90O)xe2x80x94NR3R4, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a
or
xe2x80x94SOxe2x80x94R3a
where R3 is (i) hydrogen,
(ii) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and sulfo, or
(iii) a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and C6-10 aryloxy; and
R3a is
(i) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and sulfo, or
(ii) a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and C6-10 aryloxy.
The xe2x80x9cheterocyclic groupxe2x80x9d of the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R3 or R3a includes, for example, a monovalent group formed by removing an optional hydrogen atom from a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, preferably, (i) a 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring or (iii) a 7- to 10-membered bridged heterocyclic ring.
The above-mentioned xe2x80x9c5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ringxe2x80x9d includes, for example, an aromatic heterocyclic ring such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, phenoxathiine, pyrrole, imidazole, pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, phthalimide, etc.; and a ring as formed through condensation of those rings, preferably a monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., benzene ring, etc.), etc.
The above-mentioned xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d includes, for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, etc.
The above-mentioned xe2x80x9c7- to 10-membered bridged heterocyclic ringxe2x80x9d includes, for example, quinuclidine, 7-azabicyclo[2,2,1]heptane, etc.
Preferable examples of the xe2x80x9cheterocyclic groupxe2x80x9d include, for example, a 5- to 10-membered (monocyclic or bicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Concretely mentioned are an aromatic heterocyclic group such as 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-isoindolylnyl, etc; and a non-aromatic heterocyclic group such as 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino, etc.
Among these groups, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Concretely mentioned are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino, etc.
The xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents which the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d mentioned above may have. When the number of substituents is two or more, those substituents may be the same as or different from one another.
In the case that the xe2x80x9csubstituentxe2x80x9d for the above xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d is xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cacyloxyxe2x80x9d, preferred xe2x80x9cacylxe2x80x9d for these xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cacyloxyxe2x80x9d is a group of the formula:
xe2x80x94(Cxe2x95x90O)xe2x80x94R3, xe2x80x94(Cxe2x95x90O)xe2x80x94OR3, xe2x80x94(Cxe2x95x90O)xe2x80x94NR3R4, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a
or
xe2x80x94SOxe2x80x94R3a
where R3 is
(i) hydrogen,
(ii) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and sulfo, or
(iii) a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and C6-10 aryloxy; and
R3a is
(i) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and sulfo, or
(ii) a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and C6-10 aryloxy.
The xe2x80x9cC1-6 alkylxe2x80x9d for R4 includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
The xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d formed by, taken together with the adjacent nitrogen atom, R3 and R4 includes, for example, a 5- to 7-membered nitrogen-containing heterocyclic ring having one nitrogen atom and optionally having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Such examples include piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, etc.
Preferably, the above xe2x80x9cacylxe2x80x9d is, for example, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-10 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C6-10 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocycle carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocycle carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C6-10 arylsulfonyl (e.g., benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.), etc.
The above-mentioned xe2x80x9cacylaminoxe2x80x9d includes, for example, an amino substituted by 1 or 2 xe2x80x9cacylxe2x80x9d described in detail in the foregoing referring to the xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d. Preferred is an acylamino of the formula:
xe2x80x94NR5COR6, xe2x80x94NR5COOR6a or xe2x80x94NR5SO2R6a
wherein R5 represents hydrogen or C1-6 alkyl, R6 represents hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R6a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
The xe2x80x9cC1-6 alkylxe2x80x9d for R5 includes the xe2x80x9cC1-6 alkylxe2x80x9d shown by R4 above.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R6 or R6a include the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d shown by R3, respectively.
Preferred examples of the xe2x80x9cacylaminoxe2x80x9d are formylamino, C1-6 alkyl-carboxamido (e.g., acetamido, etc.), C6-10 aryl-carboxamido (e.g., phenylcarboxamido, naphthylcarboxamido, etc.), C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), etc.
The above-mentioned xe2x80x9cacyloxyxe2x80x9d includes, for example, an oxy substituted by one xe2x80x9cacylxe2x80x9d described in detail in the foregoing referring to the xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d. Preferred is an acyloxy of the formula:
xe2x80x94Oxe2x80x94COR7, xe2x80x94Oxe2x80x94COOR7
or
xe2x80x94Oxe2x80x94CONHR7
wherein R7 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R7 include the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d shown by R3, respectively.
Preferred examples of the xe2x80x9cacyloxyxe2x80x9d are C1-6 alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), C6-10 aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-10 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, etc.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d for Ar preferably includes halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino and formyl.
The xe2x80x9cfused aromatic groupxe2x80x9d of the xe2x80x9cfused aromatic group which may be substitutedxe2x80x9d for Ar is meant to indicate a monovalent group by removing an optional hydrogen atom from a fused polycyclic (preferably bi-cyclic to tetra-cyclic, more preferably bi-cyclic or tri-cyclic) aromatic ring. The xe2x80x9cfused polycyclic aromatic ringxe2x80x9d includes a fused polycyclic aromatic hydrocarbon group, a fused polycyclic aromatic heterocyclic ring, etc.
The xe2x80x9cfused polycyclic aromatic hydrocarbon groupxe2x80x9d includes, for example, a fused polycyclic (preferably bi-cyclic or tri-cyclic) C10-14 aromatic hydrocarbon group (e.g., naphthalene, indene, anthracene, etc.).
The xe2x80x9cfused polycyclic aromatic heterocyclic ringxe2x80x9d includes, for example, a 9- to 14-membered, preferably 9- or 10-membered fused polycyclic aromatic heterocyclic ring containing one or more (e.g., 1 to 4) hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Concretely mentioned is an aromatic heterocyclic ring such as benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalimide, etc.
As specific examples of the xe2x80x9cfused aromatic groupxe2x80x9d, mentioned are 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-benzimidazolyl, 1-indolyl, 2-indolyl, 3-indolyl, etc. Preferred are 1-naphthyl and 2-naphthyl, etc.
For the xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9cfused aromatic group which may be substitutedxe2x80x9d and their number, referred to are the same as those mentioned above for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d for Ar.
Ar is preferably an aromatic ring assembly group which may be substituted. Among others, the aromatic ring assembly group is preferably composed of two or three aromatic rings selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran. More preferred is 2-, 3- or 4-biphenylyl.
Preferred examples of Ar are aromatic ring assembly groups which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy. More preferred is a 2-, 3- or 4-biphenylyl (but even more preferably, 4-biphenylyl) which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy.
The xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d for Arxe2x80x2 includes, for example, a monocyclic aromatic group, an aromatic ring assembly group, a fused aromatic group, etc. The xe2x80x9caromatic ring assembly groupxe2x80x9d and the xe2x80x9cfused aromatic groupsxe2x80x9d are the same as those mentioned in detail hereinabove for the xe2x80x9caromatic ring assembly groupxe2x80x9d and the xe2x80x9cfused aromatic groupsxe2x80x9d for Ar.
The xe2x80x9cmonocyclic aromatic groupxe2x80x9d includes, for example, a monovalent group by removing an optional hydrogen atom from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring.
The xe2x80x9c5- or 6-membered aromatic heterocyclic ringxe2x80x9d includes, for example, a 5- or 6-membered aromatic heterocyclic ring containing one or more (e.g., 1 to 3) hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Concretely mentioned are thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, etc.
Specific examples of the xe2x80x9cmonocyclic aromatic groupxe2x80x9d are phenyl, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- or 4-pyrazolyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, etc.
The xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9caromatic group which may be substitutedxe2x80x9d and their number are the same as those mentioned above for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d for Ar.
Arxe2x80x2 is preferably an aromatic ring assembly group which may be substituted, or a fused aromatic group which may be substituted. More preferred is an aromatic ring assembly group which may be substituted.
The xe2x80x9cC1-6 alkylenexe2x80x9d of the xe2x80x9cC1-6 alkylene which may be substituted by 1 to 3 substituents selected from the group consisting of oxo and C1-6 alkylxe2x80x9d for X includes, for example, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, etc.
The xe2x80x9cC2-6 alkenylenexe2x80x9d of the xe2x80x9cC2-6 alkenylene which may be substituted by 1 to 3 substituents selected from the group consisting of oxo and C1-6 alkylxe2x80x9d for X includes, for example, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, etc.
The xe2x80x9cC2-6 alkynylenexe2x80x9d of the xe2x80x9cC2-6 alkynylene which may be substituted by 1 to 3 substituents selected from the group consisting of oxo and C1-6 alkylxe2x80x9d for X includes, for example, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x95x90Cxe2x80x94CH2xe2x80x94CH2xe2x80x94, etc.
The above oxo and C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) may be substituted at the substitutable positions. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cacylxe2x80x9d for R8 are the same as those mentioned in detail above. R8 is preferably hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, etc.
X is preferably a C1-6 alkylene (e.g., xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, etc.); a group of the formula:
xe2x80x94(CH2)p-X1xe2x80x94
or
xe2x80x94SO2xe2x80x94NR8xe2x80x94
wherein each symbol is as defined above; etc. Of those, more preferably, X1 is O or NR8 (more preferably O); and R8 is hydrogen or a C1-3 alkyl-carbonyl (e.g., acetyl, etc.).
X is preferably a divalent C1-6 aliphatic hydrocarbon group (e.g., C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, etc.) which may contain an oxygen atom, more preferably a C1-3 alkylene, xe2x80x94CH2xe2x80x94Oxe2x80x94, etc.
The xe2x80x9cdivalent C1-6 aliphatic hydrocarbon group which may contain an oxygen atom or a sulfur atomxe2x80x9d of the xe2x80x9cdivalent C1-6 aliphatic hydrocarbon group which may have an oxygen atom or a sulfur atom and may be substitutedxe2x80x9d for Y includes, for example, a saturated or unsaturated divalent C1-6 aliphatic hydrocarbon group which may contain one or two, preferably one oxygen or sulfur atom at any position between carbon atoms or at the terminal. Concretely mentioned are a C1-6 alkylene, a C2-6 alkenylene, a C2-6 alkynylene, a group of the formula:
xe2x80x94(CH2)m-Y1xe2x80x94(CH2)n-
wherein xe2x80x94Y1xe2x80x94 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94; m represents an integer of 0 to 4; n represents an integer of 1 to 5; and m+n is an integer of 1 to 5, etc. Preferred is a divalent C1-6 aliphatic hydrocarbon group.
The above xe2x80x9cC1-6 alkylenexe2x80x9d, xe2x80x9cC2-6 alkenylenexe2x80x9d and xe2x80x9cC2-6 alkynylenexe2x80x9d are the same as those mentioned in detail above for the xe2x80x9cC1-6 alkylenexe2x80x9d, xe2x80x9cC2-6 alkenylenexe2x80x9d and xe2x80x9cC2-6 alkynylenexe2x80x9d for X.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cdivalent C1-6 aliphatic hydrocarbon group which may contain an oxygen atom or a sulfur atom and may be substitutedxe2x80x9d includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc. One to three such substituents may be substituted at the substitutable positions of the divalent C1-6 aliphatic hydrocarbon group. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
Y is preferably a divalent C1-6 aliphatic hydrocarbon group, more preferably a C1-6 alkylene.
The xe2x80x9clower alkylxe2x80x9d of the xe2x80x9clower alkyl which may be substitutedxe2x80x9d for R1 or R2 includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc. Preferred is methyl, ethyl and propyl.
The xe2x80x9clower alkyl group which may be substitutedxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents, such as (1) those which the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d may have or (2) C6-10 aryl. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
The xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d of the xe2x80x9cnitrogen-containing heterocyclic ring which may be substitutedxe2x80x9d to be formed by R1 and R2 along with the adjacent nitrogen atom includes, for example, a 3- to 8-membered nitrogen-containing heterocyclic ring having one nitrogen atom and optionally having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Concretely mentioned are aziridine, azetidine, morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, as well as unsaturated cyclic amines corresponding to those rings (e.g., 1,2,5,6-tetrahydropyridine, etc.), etc. Of those, preferred are morpholine, piperidine, piperazine, pyrrolidine, etc.
The xe2x80x9cnitrogen-containing heterocyclic ring which may be substitutedxe2x80x9d may have 1 to 3 substituents selected from the group consisting of (1) xe2x80x9csubstituentsxe2x80x9d for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d, (2) oxo and (3) C7-19 aralkyl. Preferred examples of the substituents are C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), 5- to 7-membered cyclic amino (e.g., morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethylenimin-1-yl, etc.), C1-6 alkyl-carboxamido (e.g., acetamido, etc.), C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, etc.), aromatic group which may be substituted (e.g., a C6-10 aryl (preferably, phenyl or 1- or 2-naphthyl) or 5- or 6-membered aromatic heterocyclic group (preferably, 2-, 3- or 4-pyridyl), each of which group may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, cyano, C1-6 alkyl and C1-6 alkoxy, etc.), oxo, etc.
R1 and R2 each is preferably C1-6 alkyl.
The xe2x80x9cgroup of the formula:
xe2x80x94Xxe2x80x94Arxe2x80x9d
is substituted at the substitutable position of Ring A. The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cbenzene ring which may be further substituted apart from the group of the formula:
xe2x80x94Xxe2x80x94Ar
wherein each symbol is as defined abovexe2x80x9d for Ring A includes, for example, halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, hydroxy, amino, etc. The xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d and the xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d are the same as those mentioned in detail above for the xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d and the xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d for Ar.
One to three such substituents may be substituted at the substitutable positions of Ring A. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
Ring A is preferable a benzene ring substituted by the group of the formula:
xe2x80x94Xxe2x80x94Ar
wherein each symbol is as defined above.
The xe2x80x9cgroup of the formula:
xe2x80x94Yxe2x80x94NR1R2xe2x80x9d
is substituted at the substitutable position of Ring B. The xe2x80x9c4- to 8-membered ringxe2x80x9d of the xe2x80x9c4- to 8-membered ring which may be further substituted apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
wherein each symbol is as defined abovexe2x80x9d for Ring B may have one double bond apart from the part at which Ring B is condensed with Ring A, and includes a 4- to 8-membered carbocyclic or heterocyclic ring which may contain 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Specific examples of those rings, mentioned is a ring of the formula: 
wherein ----- represents a single bond or a double bond; and Z represents (i) a bond, (ii) a C1-4 alkylene, (iii) a C2-4 alkenylene, (iv) xe2x80x94Oxe2x80x94CH2xe2x80x94, (v) xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 or (vi) a group of the formula:
xe2x80x94NR8axe2x80x94CH2xe2x80x94
or
xe2x80x94NR8axe2x80x94CH2xe2x80x94CH2xe2x80x94
wherein R8a has the same meaning as R8.
R8a is preferably hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, etc. More preferred is hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, C1-3 alkylsulfonyl, etc.
Z is preferably C1-3 alkylene, xe2x80x94NR8axe2x80x94CH2xe2x80x94, etc. More preferably, it is ethylene.
The xe2x80x9c4- to 8-membered ringxe2x80x9d is preferably a 4- to 8-membered ring of the formula: 
wherein Z has the same meanings as above. More preferred is a 6-membered carbocyclic or heterocyclic ring which does not have any double bond apart from the part at which it is condensed with Ring A, and which may have one oxygen atom or imino in addition to carbon atoms.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9c4- to 8-membered ring which may be further substituted apart from the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
wherein each symbol is as defined abovexe2x80x9d includes, for example, oxo, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc. One to three such substituents may be substituted at the substitutable positions of the ring. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
Ring B is preferably a 6-membered carbocyclic or heterocyclic ring substituted by the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
wherein each symbol is as defined above. More preferably Ring B is a ring of the formula: 
wherein Za represents C1-3 alkylene or a group of the formula:
xe2x80x94NR8cxe2x80x94CH2xe2x80x94
wherein R8c is hydrogen, optionally halogenated C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C1-6 alkylsulfonyl or C6-10 arylsulfonyl; and the other symbols have the same meanings as above. Of those, Za is preferably ethylene.
The fused ring to be formed by Ring A and Ring B is preferably a ring of the formula: 
In compounds (I) and (Ixe2x80x2), preferred is a compound wherein Ar and Arxe2x80x2 each is an aromatic ring assembly group (preferably 2-, 3- or 4-biphenylyl) which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, formyl and C1-6 alkyl-carboxamido;
X is C1-3 alkylene which may contain an oxygen atom;
Y is C1-6 alkylene;
R1 and R2 each is C1-6 alkyl;
Ring A is a benzene ring substituted by the group of the formula:
xe2x80x94Xxe2x80x94Ar
xe2x80x83wherein each symbol is as defined above; and
Ring B is a 6-membered carbocyclic or heterocyclic ring substituted by the group of the formula:
xe2x80x94Yxe2x80x94NR1R2
xe2x80x83wherein each symbol is as defined above.
More preferred is a compound of the formula: 
wherein R0 is 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, formyl and C1-6 alkyl-carboxamido; and
R1a and R2a each is C1-6 alkyl.
Also preferred is a compound of the formula: 
wherein Ara is (i) 2, 3- or 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, amino, formyl and C1-6 alkyl-carboxamido, (ii) 4-(2-thienyl)phenyl or 4-(3-thienyl) phenyl, (iii) 4-(3-pyridyl)phenyl, (iv) 6-phenyl-3-pyridyl which may be substituted by a C1-6 alkoxy, (v) 5-phenyl-1,3,4-oxadiazol-2-yl, (vi) 4-(2-naphthyl) phenyl, (vii) 4-(2-benzofuranyl)phenyl, (viii) 1- or 2-naphthyl, (ix) 2-quinolyl, (x) 2-benzothiazolyl or (xi) 2-benzofuranyl;
Xxe2x80x2 is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94 or a group of the formula:
xe2x80x94CH2xe2x80x94NR8xe2x80x2xe2x80x94
xe2x80x83wherein R8xe2x80x2 is hydrogen or C1-3 alkyl-carbonyl;
Yxe2x80x2 is C1-6 alkylene;
Zxe2x80x2 is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or a group of the formula:
xe2x80x94NR8xe2x80x3xe2x80x94CH2xe2x80x94
xe2x80x83wherein R8xe2x80x3 is hydrogen, C1-3 alkyl, C1-3 alkyl-carbonyl or C1-3 alkylsulfonyl; and
R1xe2x80x2 and R2xe2x80x2 each is C1-6 alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of di-C1-3 alkylamino, C1-3 alkoxy-carbonyl and phenyl, or
R1xe2x80x2 and R2xe2x80x2 form, taken together with the adjacent nitrogen atom, a pyrrolidin-1-yl, piperidino or piperazin-1-yl which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, C1-3 alkoxy-carbonyl, piperidino, phenyl and benzyl.
Especially preferred are 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino) methyltetralin,
2-(N,N-dimethylamino)methyl-6-(4xe2x80x2-methoxybiphenyl-4-yl) methoxytetralin,
(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino) ethyl]tetralin,
(+)-2-[2-(N,N-dimethylamino)ethyl]-6-(4xe2x80x2-methylbiphenyl-4-yl) methoxytetralin,
(+)-2-[2-(N,N-dimethylamino)ethyl]-6-(4xe2x80x2-methoxybiphenyl-4-yl) methoxytetralin,
(+)-6-(2xe2x80x2,4xe2x80x2-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
(+)-6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin,
(+)-6-(3xe2x80x2,4xe2x80x2-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin and salts thereof.
As the salts of compound (I) and compound (Ixe2x80x2), for example, inorganic salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids can be mentioned. Preferable examples of inorganic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; aluminum salts, etc. Preferred salts with organic bases are exemplified by salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. Preferred salts with inorganic acids are exemplified by salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred salts with organic acids are exemplified by salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferred salts with basic amino acids are exemplified by salts with arginine, lysine, ornithine, etc. Preferred salts with acidic amino acids are exemplified by salts with aspartic acid, glutamic acid, etc.
Among others, pharmaceutically acceptable salts are preferable. Preferable examples include, for example, when compound (I) or (ixe2x80x2) has a acidic functional group, alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts; and when compound (I) or (Ixe2x80x2) has a basic functional group, inorganic salts such as hydrochloride, sulfate, phosphate and hydrobromide, or, organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate and tartrate.
Process for producing compound (I) is mentioned below.
Compound (I) can be produced by any per se known means, for example, by the following processes 1 to 4, etc. Compound (Ixe2x80x2) can be produced in accordance with the production of compound (I).
Compounds described in the following processes 1 to 4 include their salts. For their salts, for example, referred to are the same as the salts of compound (I).
xe2x80x9cRoom temperaturexe2x80x9d is meant to indicate a temperature falling between 0xc2x0 C. and 30xc2x0 C.
For example, compound (I) wherein X contains an oxygen atom, a sulfur atom which may be oxidized (S, SO or SO2) or a group of the formula:
NR8a
wherein R8a has the same meanings as above, is produced according to the methods mentioned below. Other compound (I) wherein X contains none of an oxygen atom, a sulfur atom which may be oxidized and a group of the formula:
NR8a
wherein R8a has the same meanings as above, can also be produced in the same manner.
Unless otherwise specifically indicated, the symbols in the chemical structures in the schemes mentioned below have the same meanings as above.

In those formulae, Xa represents an oxygen atom, a sulfur atom which may be oxidized or a group of the formula:
NR8a
wherein R8a has the same meanings as above.
Step 1
Compound (II) is subjected to alkylation or acylation to obtain compound (Ia).
The xe2x80x9calkylationxe2x80x9d and xe2x80x9cacylationxe2x80x9d may be effected in any per se known manner, for example, according to the methods described in Organic Functional Group Preparations, 2nd Ed., Academic Press Inc., 1989.
Concretely, compound (II) is reacted with a compound of the formula:
Arxe2x80x94Xb-L
wherein Xb represents a group formed by removing Xa from X, and L represents a leaving group or a hydroxy, to obtain compound (Ia).
The xe2x80x9cleaving groupxe2x80x9d for L includes, for example, halogen atoms (e.g., chloro, bromo, iodo, etc.), optionally halogenated C1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C6-10 arylsulfonyloxy which may be substituted, etc. The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cC6-10 arylsulfonyloxy which may be substitutedxe2x80x9d includes, for example, 1 to 3 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy. Specific examples of the xe2x80x9cC6-10 arylsulfonyloxy which may be substitutedxe2x80x9d are benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy, etc.
Compound (II) can be produced in any per se known manner, for example, according to the methods of the following schemes 2 to 4 or analogous methods thereto.
In the case that L is a leaving group, for example, compound (II) is reacted with an equivalent amount or an excessive amount of a compound of the formula:
Arxe2x80x94Xb-L
wherein each symbol is as defined above, in an inert solvent. If desired, a base is added to the reaction system. Where Xa is a group of the formula:
NR8a
wherein R8a has the same meanings as above, the addition of the base is not always indispensable.
The reaction temperature falls between xe2x88x9220xc2x0 C. and 100xc2x0 C., preferably between room temperature (0xc2x0 C. to 30xc2x0 C.) and 80xc2x0 C. The reaction time falls between 0.5 hours and 1 day.
The inert solvent includes, for example, alcohols, ethers, halogenated hydrocarbons, aromatic solvents, nitrites, amides, ketones, sulfoxides, water, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are acetonitrile, N,N-dimethylformamide (DMF), acetone, ethanol, pyridine, etc.
The xe2x80x9cbasexe2x80x9d includes, for example;
(1) strong bases such as alkali metal or alkaline earth metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (e.g., lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal lower-alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc.;
(2) inorganic bases such as alkali metal or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogencarbonates (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), etc.; or
(3) organic bases such as amines e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), etc., basic heterocyclic compounds, e.g., pyridine, imidazole, 2,6-lutidine, etc.
Preferably, the alkylation is effected by stirring compound (II) with 1 to 2 equivalents of a compound of the formula:
Arxe2x80x94Xb-L
wherein each symbol is as defined above, and 1 to 5 equivalents of a base (e.g., potassium carbonate, sodium hydride, sodium hydroxide, etc.), in acetonitrile or DMF, for 1 to 20 hours. The preferred reaction temperature varies, depending on the base used. For example, when sodium hydride is used, the reaction temperature is preferably room temperature; and when potassium carbonate is used, the preferred reaction temperature falls between room temperature and 80xc2x0 C.
The acylation is preferably effected by stirring compound (II) with 1 to 1.5 equivalents of a compound of the formula:
Arxe2x80x94Xb-L
wherein each symbol is as defined above, and 1 to 5 equivalents of a base (e.g., sodium hydride, sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, triethylamine, etc.), in an inert solvent (e.g., single or mixed solvent of water, ethyl acetate, DMF, acetonitrile and/or pyridine), at room temperature for 1 to 6 hours.
In the case that L is a hydroxy group, compound (II) is subjected to Mitsunobu reaction.
The Mitsunobu reaction may be attained, for example, by stirring compound (II) with 1 to 3 equivalents, preferably from 1.1 to 2 equivalents of a compound of the formula:
Arxe2x80x94Xb-L
wherein each symbol is as defined above, in the presence of 1 to 2 equivalents of a triarylphosphine (e.g., triphenylphosphine, etc.) and 1 to 2 equivalents of DEAE (diethyl azodicarboxylate) in an inert solvent, for 1 to 24 hours.
The inert solvent includes, for example, ethers, etc. Preferred is tetrahydrofuran (THF). 
In those formulae, W represents a hydrogen atom or a protective group; and Ya represents a group formed by removing a methylene from Y.
For the xe2x80x9cprotective groupxe2x80x9d for W, referred to are the same as those for the xe2x80x9cprotective group for hydroxy groupxe2x80x9d which will be mentioned hereinafter. W is preferably a C1-6 alkyl or a benzyl which may be substituted.
Step 2
Compound (III) is subjected to amidation to obtain compound (IV).
Compound (III) is an easily-available known compound. Examples for the production of compound (II) are disclosed in JP-A-2-96552, JP-A-6-206851, J. Med. Chem., 1326 (1989), etc.
The production of some specific examples of compound (III) wherein Xa is-an oxygen atom and W is a methyl, is disclosed in other references. For example,
(1) methods for producing 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-acetic acid are disclosed in Synthetic Communications 11, 803-809 (1981), etc.; and
(2) methods for producing 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-carboxylic acid and 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-butyric acid are disclosed in J. Chem. Soc. Perkin Trans. I, 1889-1893 (1976), etc.
The production or some other examples of compound (III) wherein Xa is an imino and W is hydrogen, 6-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid and its ethyl ester is disclosed in Zhur. Obschch. Khim., p. 1446 (1952), etc.
In other case that compound (III) which is 7-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-acetic acid or 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-carboxylic acid, it can be produced according to the methods described in J. Am. Chem. Soc., 77, 5932-5933 (1955) or analogous methods thereto. Compound (III) which is 7-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid can be produced according to the methods described in JP-A-7-126267.
The xe2x80x9camidationxe2x80x9d may be effected in any per se known methods, for example, (1) by reacting compound (III) with a compound of the formula:
HNR1R2
in the presence of a dehydrating condensing agent, or (2) by reacting a reactive derivative of compound (III) with a compound of the formula:
HNR1R2.
In the above reaction (1), compound (III) is reacted with 1 to 5 equivalents of a compound of the formula:
HNR1R2
in the presence of 1 to 2 equivalents of a dehydrating condensing agent, in an inert solvent, at room temperature, for 10 to 24 hours. If desired, 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOBT) and/or 1 to 5 equivalents of a base (e.g., triethylamine, etc.) may be added to the reaction system.
The xe2x80x9cdehydrating condensing agentxe2x80x9d includes, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), etc. Of those, preferred is WSC.
The inert solvent includes, for example, nitrites (preferably, acetonitrile), amides (preferably, DMF), halogenated hydrocarbons (preferably, dichloromethane), ethers (preferably, THF), etc., which may be used either singly or as a suitable mixture of two or more species.
In the above reaction (2), a reactive derivative of compound (III) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents of a compound of the formula:
HNR1R2,
in an inert solvent, at xe2x88x9220 to 50xc2x0 C., preferably at room temperature, for 5 minutes to 40 hours, preferably 1 to 18 hours. If desired, 1 to 10 equivalents, preferably 1 to 3 equivalents of a base may be in the reaction system.
The xe2x80x9creactive derivativexe2x80x9d of compound (III) includes, for example, its acid halides (e.g., acid chlorides, acid bromides, etc.), mixed acid anhydrides (e.g., acid anhydrides with C1-6 alkyl-carboxylic acids, C6-10 aryl-carboxylic acids or C1-6 alkyl-carbonic acids, etc.), and active esters (e.g., esters with phenol which may be substituted, 1-hydroxybenzotriazole or N-hydroxysuccinimide, etc.). The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cphenol which may be substitutedxe2x80x9d includes, for example, 1 to 5 substituents selected from the group consisting of halogen atoms, nitro, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy. Specific examples of the xe2x80x9cphenol which may be substitutedxe2x80x9d are phenol, pentachlorophenol, pentafluorophenol, p-nitrophenyl, etc. The reactive derivatives are preferably acid halides.
The xe2x80x9cbasexe2x80x9d is the same as those mentioned in detail hereinabove for the step 1. Preferred are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, etc. The inert solvent includes, for example, ethers, halogenated hydrocarbons, aromatic solvents, nitrites, amides, ketones, sulfoxides, water, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are acetonitrile, dichloromethane, chloroform, etc.
Step 3
Compound (IV) is subjected to reduction to obtain compound (V).
The reduction may be effected in any per se known manner, for example, according to the methods described in Organic Functional Group Preparations, 2nd Ed., Academic Press Inc., 1989, etc. Concretely, for example, (1) compound (IV) is reacted with a metal hydride; (2) compound (IV) is reacted with a metal; or (3) compound (IV) is subjected to catalytic reduction.
In the reaction (1), compound (IV) is reacted with 1 to 20 equivalents, preferably 1 to 6 equivalents of a metal hydride in an inert solvent.
The xe2x80x9cmetal hydridexe2x80x9d includes, for example, aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium borohydride cyanide, lithium borohydride cyanide, borane complexes (e.g., borane-THF complex, catechol-borane, etc.), dibutyl aluminum hydride, as well as mixtures of those metal hydrides and Lewis acids (e.g., aluminum chloride, titanium tetrachloride, cobalt chloride, etc.) or phosphorus oxychloride, etc. Preferred metal hydrides are lithium aluminum hydride and aluminum hydride.
The inert solvent includes, for example, ethers.
The reaction temperature varies, depending on the metal hydride used, but generally falls between xe2x88x9270 and 100xc2x0 C. Where lithium aluminum hydride is used, the reaction temperature may be between room temperature and 80xc2x0 C. Where borane complex is used, the reaction temperature may be between room temperature and 100xc2x0 C., preferably between room temperature and 60xc2x0 C.
The reaction time falls between 1 and 48 hours.
In the reaction (2), compound (IV) is reacted with 1 to 20 equivalents, preferably 2 to 6 equivalents of a metal in an inert solvent.
The xe2x80x9cmetalxe2x80x9d includes, for example, zinc, iron, sodium, potassium, etc.
The inert solvent includes, for example, organic acids (e.g., acetic acid, propionic acid, methanesulfonic acid, etc.), ethers, aromatic solvents, hydrocarbons, etc., which may be used either singly or as a suitable mixture of two or more species. Preferred are ethers.
The reaction temperature varies, depending on the metal used, but generally falls between xe2x88x9270 and 100xc2x0 C. Where zinc is used, the reaction temperature may fall between room temperature and 80xc2x0 C.
The reaction time falls between 1 and 10 hours.
In the reaction (3), compound (IV) is reacted with a catalytic amount to 10 equivalents of a metal catalyst (e.g., Raney nickel, etc.) and a phosphorus sulfide compound (e.g., phosphorus pentasulfide, phosphorus trisulfide, etc.), in an inert solvent (e.g., alcohols, etc.), at room temperature to 100xc2x0 C. under a hydrogen pressure of 1 to 100 atmospheres, for 1 to 48 hours.
In the above step 3, by selecting the reaction condition for the reduction, a carbonyl group and a lactam which are functional groups in the molecule (IV), are reduced to give a hydroxy and a cyclic amino, respectively.
In the case that the fused ring formed by Ring A and Ring B is, for example, 2-oxo-1,2,3,4-tetrahydroquinoline or 2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, 1,2,3,4-tetrahydroquinoline and 2,3,4,5-tetrahydro-1H-1-benzazepine are obtained, respectively by using the above borane complexes. Concretely, compound (IV) is reacted with one equivalent to an excessive amount, preferably 1 to 5 equivalents of borane complexes in an ethers, at room temperature to 100xc2x0 C., preferably at room temperature to 60xc2x0 C., for 0.1 to 48 hours, preferably 1 to 5 hours.
Step 4
Compound (V) is subjected to deprotection to obtain compound (IIa).
Briefly, compound (V) wherein W is a protective group is subjected to deprotection in per se known manner.
The deprotection may be effected, for example, according to the methods described in Organic Functional Group Preparations mentioned above, etc. Concretely, the deprotection includes, for example, deprotection by acid, catalytic reduction, hydrolysis, nucleophilic substitution, etc., which may be suitably selected in accordance with the protective group W.
In the case that W is C1-6 alkyl, preferably methyl, for example, compound (V) is reacted with 1 to 100 equivalents of an acid in the absence or presence of an insert solvent, at xe2x88x9278 to 200xc2x0 C., for 5 minutes to 24 hours.
The acid includes, for example, mineral acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), Lewis acids (e.g., aluminum chloride, boron tribromide, etc.), and halogenated silane reagents (e.g., iodotrimethylsilane, bromotrimethylsilane, etc.).
The inert solvent includes, for example, water, halogenated hydrocarbons, acetic acid, etc., which may be used either singly or as a suitable mixture of two or more species.
Preferably, compound (V) is reacted with 5 to 100 equivalents of hydrobromic acid in water or acetic acid, at 100 to 130xc2x0 C., for 1 to 5 hours.
In the case that W is a benzyl which may be substituted, for example, compound (V) is subjected to catalytic reduction in general.
Briefly, compound (V) is reacted with a catalytic amount of a metal catalyst (e.g., Raney nickel, platinum hydroxide, palladium metal, palladium-carbon, etc.), in an inert solvent (e.g., alcohols, etc.), at room temperature to 100xc2x0 C., under a hydrogen pressure of 1 to 100 atmospheres, for 1 to 48 hours. Preferably, compound (V) is reacted with a catalytic amount of palladium-carbon, in alcohols (e.g., ethanol, etc.), under a hydrogen pressure of 1 to 10 atmospheres, at room temperature to 50xc2x0 C., for 1 to 10 hours.
In the case that W is C16 alkyl-carbonyl, a benzoyl or a C7-10 aralkyl-carbonyl, for example, compound (V) is subjected to hydrolysis.
Briefly, compound (V) is reacted with 2 to 100 equivalents, preferably 5 to 10 equivalents of an alkali in an inert solvent, at room temperature to 120xc2x0 C., preferably at room temperature to 60xc2x0 C., for 5 minutes to 100 hours, preferably for 1 to 20 hours.
The alkali includes, for example, hydroxides of inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. Of those, preferred is sodium hydroxide.
The inert solvent includes, for example, water, alcohols, ethers, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred is a mixed solvent of water-methanol.
Preferably, the solvent is a mixed solvent of water-methanol, the reaction temperature falls between room temperature and 60xc2x0 C., and the reaction time falls between 5 and 10 hours. 
In those formulae, R9 represents a protective group for carboxy; and L represents a leaving group.
The xe2x80x9cprotective group for carboxyxe2x80x9d for R9 are the same as those for the xe2x80x9cprotective group for carboxyxe2x80x9d which will be mentioned hereinafter. R9 is preferably a C1-6 alkyl.
The xe2x80x9cleaving groupxe2x80x9d for L are the same as those mentioned above for L.
Step 5
Compound (VI) is subjected to reduction to obtain compound (VII).
Compound (VI) is easily available, and can be obtained, for example, by subjecting compound (III) to esterification in per se known manner.
The reduction may be effected in any per se known manner, for example, according to the methods described in Organic Functional Group Preparations mentioned above, etc. For the reaction condition for the reduction, referred to is the same as that for the step 3. Preferably employed are metal hydrides.
Concretely, for example, compound (VI) is reacted with 1 to 20 equivalents, preferably 1 to 6 equivalents of a metal hydride (preferably, lithium aluminum hydride) in an inert solvent.
The inert solvent includes, for example, ethers, alcohols, aromatic solvents, etc., which may be used either singly or as a suitable mixture of two or more species.
The reaction temperature varies, depending on the metal hydride used, but, in general, falls between xe2x88x9270 and 100xc2x0 C. Where lithium aluminum hydride is used, the reaction temperature is preferably between room temperature and 50xc2x0 C.
Step 6
A leaving group is introduced into compound (VII) to obtain compound (VIII).
In the case that L is a halogen in compound (VIII), compound (VII) is reacted with a halogenating reagent.
For example, where a commercially-available halogenating reagent (e.g., hydrobromic acid, phosphorus tribromide, phosphorus pentabromide, thionyl chloride, etc.) is used as a halogenating reagent, the halogenation may be effected in any per se known manner. For example, where hydrobromic acid is used as a halogenating reagent, compound (VII) may be reacted with 1.5 to 5 equivalents of the hydrobromic acid at 80 to 130xc2x0 C. for 1 to 18 hours.
Where the halogenating reagent is prepared, 1 to 1.5 equivalents of bromine or iodine is mixed with the same amount of triphenylphosphine in an inert solvent (e.g., nitrites, ethers, etc.) at room temperature to give a halogenating reagent. The thus-prepared halogenating reagent is reacted with compound (VII) in the same solvent at room temperature for 0.5 to 18 hours, preferably from 0.5 to 3 hours.
In the case that L is a sulfonyloxy (e.g., methanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, etc.) in compound (VIII), compound (VII) is stirred with one equivalent or an excessive amount, preferably 1 to 1.5 equivalents of a sulfonating reagent (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, etc.) along with a base in an inert solvent at xe2x88x9250 to 50xc2x0 C., preferably at room temperature, for 1 to 24 hours.
The xe2x80x9cbasexe2x80x9d is the same as those mentioned in detail above for the step 1. Especially preferred are amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, etc.; and basic heterocyclic compounds such as pyridine, imidazole, 2,6-lutidine, etc. The amount of the base to be used is 1 to 8 equivalents relative to the sulfonating reagent used.
The inert solvent includes, for example, halogenated hydrocarbons, nitrites, esters, etc., which may be used either singly or as a suitable mixture of two or more species.
The sulfonyloxy group in the resultant compound (VIII) may be subjected to iodation. For this, for example, compound (VIII) is reacted with 1 to 10 equivalents, preferably 1 to 3 equivalents of sodium iodide or potassium iodide in an inert solvent (e.g., ketones, ethers, etc.) at room temperature to 100xc2x0 C., preferably at 30 to 60xc2x0 C., for 1 to 24 hours.
Step 7
Compound (VIII) is subjected to amination to obtain compound (IX).
The amination may be effected in any per se known method, for example, according to the methods described in Organic Functional Group Preparations mentioned above, etc. Concretely, for example, compound (VIII) is stirred with 1 to 5 equivalents, preferably 1 to 2 equivalents of a compound of the formula:
HNR1R2
in an inert solvent at room temperature to 100xc2x0 C., preferably at room temperature to 50xc2x0 C., for 0.5 hours to one day. In general, 1 to 5 equivalents, preferably 1 to 3 equivalents of a base is added to the reaction system.
The xe2x80x9cbasexe2x80x9d is the same as those mentioned in detail hereinabove for the step 1. Especially preferred are tertiary amines such as triethylamine, etc.; and alkali metal or alkaline earth metal carbonates, etc.
The inert solvent includes, for example, water, alcohols, ethers, halogenated hydrocarbons, aromatic solvents, nitrites, amides, ketones, sulfoxides, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are acetonitrile, N,N-dimethylformamide (DMF), acetone, ethanol, etc.
Preferably, compound (VIII) is stirred with 1 to 2 equivalents of a compound of the formula:
HNR1R2,
along with 1 to 3 equivalents of a base (e.g., potassium carbonate, triethylamine, etc.) in an inert solvent (e.g., acetonitrile, DMF, etc.), at room temperature to 50xc2x0 C., for 10 hours to one day.
Step 8
Compound (IX) is subjected to deprotection to obtain compound (IIa).
The deprotection may be effected under the same reaction condition as that for the step 4.
Compound (II) wherein Y is a methylene may be obtained according to the following scheme 4. 
In those formulae, Ring Bxe2x80x2 corresponds to Ring B having an oxo; and R10 and R11 each represents a C1-6 alkyl or a benzyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and nitro.
Step 9
Compound (X) is subjected to Mannich reaction to obtain compound (XI).
Compound (X) is easily available, and can be produced by any per se known methods.
The Mannich reaction may be effected in any per se known manner, for example, according to the methods described in WO 92/05143, etc. Concretely, for example, compound (X) is reacted with an excessive amount of formaldehyde or paraformaldehyde and 1 to 5 equivalents, preferably 1 to 2 equivalents of a secondary amine (e.g., a compound of the formula:
HNR10R11,
etc.) or 1 to 10 equivalents, preferably 1 to 5 equivalents of a dimethylmethylene-ammonium salt (e.g., chloride, iodide, etc.), in an inert solvent, at room temperature to 80xc2x0 C., for 1 to 48 hours. If desired, an equivalent amount to an excessive amount of an acid (e.g., mineral acids such as hydrochloric acid, etc.) may be added to the reaction system.
The inert solvent includes, for example, ethers, alcohols, nitriles, water, etc., which may be used either singly or as a suitable mixture of two or more species.
In the case that R10 and R11 each is C1-6 alkyl in the compound of the formula:
HNR10R11,
thus obtained compound (XI) is directly subjected to the reaction of step 12 without being subjected to the reaction of the next step 10.
Step 10
Compound (XI) is converted into its quaternary amine salt, compound (XII).
After the previous step 9, the obtained compound (XI) is then reacted with 1 to 3 equivalents, preferably 1.1 to 1.5 equivalents of a C1-6 alkyl halide (e.g., methyl iodide, etc.) in an inert solvent (e.g., ketones, alcohols, etc.), at room temperature to a temperature for reflux, for 0.1 to 24 hours, preferably for 0.5 to 2 hours.
Step 11
Compound (XII) is subjected to amination to obtain compound (XIII).
The amination may be effected under the same reaction condition as that for the step 7. Concretely, for example, compound (XII) is stirred with 1 to 5 equivalents, preferably 1 to 3 equivalents of a compound of the formula:
HNR1R2,
in an inert solvent, at room temperature to 100xc2x0 C., preferably at room temperature to 50xc2x0 C., for 0.5 hours to one day. In general, 1 to 3 equivalents, preferably 1 to 2 equivalents of a base is added to the reaction system.
The xe2x80x9cbasexe2x80x9d is the same as those mentioned in detail hereinabove for the step 1. Especially preferred are tertiary amines such as triethylamine, etc.; and alkali metal or alkaline earth metal carbonates, etc.
The inert solvent includes, for example, water, alcohols, ethers, halogenated hydrocarbons, aromatic solvents, nitriles, amides, ketones, sulfoxides, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are acetonitrile, DMF, acetone, ethanol, etc.
Preferably, compound (XII) is stirred with 1 to 2 equivalents of a compound of the formula:
HNR1R2,
and 1 to 3 equivalents of a base (e.g., potassium carbonate, triethylamine, etc.), in an inert solvent (e.g., acetonitrile, DMF, etc.), at room temperature to 50xc2x0 C., for 10 hours to one day.
Step 12
Compound (XIII) is subjected to reduction to obtain compound (XIV) via compound (XIIIa).
The reduction may be effected in any per se known manner, for example, according to the methods described in Organic Functional Group Preparations mentioned above, etc. Concretely, for example, (1) compound (XIII) is reacted with a metal hydride, (2) compound (XIII) is reacted with a metal, or (3) compound (XIII) is subjected to catalytic reduction.
In the above reaction (1), compound (XIII) is reacted with 1 to 20 equivalents, preferably 2 to 6 equivalents of a metal hydride in an inert solvent.
The xe2x80x9cmetal hydridexe2x80x9d includes, for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium borohydride cyanide, diborane, dibutyl aluminum hydride, etc.
The inert solvent is preferably ethers when lithium aluminum hydride is used, but is preferably alcohols when sodium borohydride is used.
The reaction temperature varies, depending on the metal hydride used, but, in general, may fall between xe2x88x9270 and 100xc2x0 C., preferably between 0 and 80xc2x0 C.
The reaction time falls between 0.1 and 24 hours, preferably between 0.5 and 12 hours.
In the above reaction (2), compound (XIII) is reacted with an excessive amount, preferably 1 to 100 equivalents of a metal (e.g., zinc powder) in an inert solvent at room temperature to 100xc2x0 C. for 1 to 24 hours. In the reaction (2), as the case may be, the reduction may be further promoted to directly give compound (XIV).
The inert solvent includes, for example, organic acids (e.g., acetic acid, etc.), ethers, etc., which may be used either singly or as a suitable mixture of two or more species.
In the above reaction (3), compound (XIII) is reacted with a catalytic amount of a metal catalyst (e.g., Raney nickel, platinum oxide, palladium metal, palladium-carbon, etc.) in an inert solvent (e.g., alcohols, etc.), at room temperature to 100xc2x0 C., under a hydrogen pressure of 1 to 100 atmospheres, for 1 to 48 hours. If desired, a catalytic amount to an excessive amount of an organic acid (e.g., acetic acid, etc.) or a mineral acid (e.g., perchloric acid, hydrochloric acid, etc.) may be added to the reaction system. In the reaction (3), as the case may be, the reduction may be further promoted to directly give compound (XIV).
The compound (XIIIa) obtained herein is subjected to reductive dehydration to give compound (XIV).
The reductive dehydration may be effected in any per se known manner, for example, through catalytic reduction or using an organic silyl reagent.
For the catalytic reduction, for example, it is preferred that compound (XIIIa) is reacted with a catalytic amount of a metal catalyst (e.g., Raney nickel, platinum oxide, palladium metal, palladium-carbon, etc.) in an inert solvent (e.g., alcohols, etc.) under a hydrogen pressure of 1 to 100 atmospheres, at room temperature to 100xc2x0 C., for 1 to 48 hours. If desired, a catalytic amount to an excessive amount of an organic acid (e.g., acetic acid, etc.) or a mineral acid (e.g., perchloric acid, hydrochloric acid, etc.) may be added to the reaction system.
In the method of using an alkylsilane reagent, for example, compound (XIIIa) is reacted with an alkylsilane reagent (e.g., triethylsilane, phenyldimethylsilane, etc.) and an acid (e.g., organic acids such as trifluoroacetic acid, etc.), in the absence or presence of an inert solvent (e.g., halogenated hydrocarbons), at 0 to 100xc2x0 C., preferably at 0 to 30xc2x0 C., for 10 minutes to 24 hours.
The amount of the alkylsilane reagent to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the compound (XIIIa).
The amount of the acid to be used is a catalytic amount to an excessive amount, preferably 1 to 5 equivalents, relative to the compound (XIIIa).
Step 13
In the case that W is a protective group in compound (XIV), compound (XIV) is subjected to deprotection to obtain compound (IIb).
The deprotection may be effected under the same reaction condition as that for the step 4.

Step 14
Compound (XV) is subjected to alkylation or acylation to obtain compound (XVI).
Compound (XV) can be obtained by subjecting compound (III) wherein W is a hydrogen to esterification in any per se known manner.
The alkylation and the acylation may be effected in the same manner as in the step 1.
Step 15
Compound (XVI) is subjected to hydrolysis in any per se known manner, and then amidation to obtain compound (XVII).
The amidation may be effected in the same manner as in the step 2.
Step 16
Compound (XVII) is subjected to reduction to obtain compound (Ib).
The reduction may be effected in the same manner as in the step 3.

In the formula, L represents a leaving group.
The xe2x80x9cleaving groupxe2x80x9d for L are the same as those mentioned hereinabove.
Step 17
Compound (XVIII) is subjected to amination to obtain compound (I).
Compound (XVIII) can be produced with ease according to any known methods, for example, a method of scheme 7 mentioned below.
The amination may be effected in the same manner as in the step 7. 
Step 18
Compound (XVI) is subjected to reduction to obtain compound (XIX).
The reduction may be effected in the same manner as in the step 5.
Step 19
A leaving group is introduced into compound (XIX) to obtain compound (XVIIIa).
The introduction of the leaving group may be effected in the same manner as in the step 6.

In the formula, K represents an aromatic group which may be substituted; and G represents a halogen atom (e.g., bromo, iodo), or a trifluoromethanesulfonyloxy.
For the xe2x80x9caromatic group which may be substitutedxe2x80x9d for K, referred to is the same as those mentioned hereinabove for the xe2x80x9caromatic group which may be substitutedxe2x80x9d for Arxe2x80x2.
Step 20
Compound (II) is subjected to the same reaction as in the step 1 to obtain compound (XX).
Step 21
Compound (XX) is subjected to aryl-coupling reaction to obtain compound (Ic).
The aryl-coupling reaction may be effected in any per se known manner, for example, according to the methods described in Acta. Chemica Scandinavia, 221-230 (1993), etc. Concretely, for example, compound (XX) is reacted with 1 to 2 equivalents of an aryl metal compound and 1 to 10 equivalents of a base, in the presence of 0.01 to 1 equivalent, preferably 0.01 to 0.5 equivalents of a transition metal catalyst, in an inert solvent, at room temperature to 150xc2x0 C., preferably at 80 to 150xc2x0 C., for 1 to 48 hours.
The xe2x80x9caryl metal compoundxe2x80x9d includes, for example, aryl-boric acid derivatives, aryl-zinc derivatives, etc.
The xe2x80x9cbasexe2x80x9d includes, for example, an aqueous solution of sodium carbonate, sodium hydrogencarbonate or the like.
The xe2x80x9ctransition metal catalystxe2x80x9d includes, for example, palladium catalysts, nickel catalysts, etc. The xe2x80x9cpalladium catalystsxe2x80x9d include, for example, tetrakis(triphenylphosphine)palladium(0), palladium acetate, bis(triphenylphosphine)palladium(II) chloride, palladium-carbon, etc. The xe2x80x9cnickel catalystsxe2x80x9d include, for example, tetrakis(triphenylphosphine)nickel(0), etc.
The inert solvent includes, for example, water, alcohols, aromatic solvents, etc., which may be used either singly or as a suitable mixture of two or more species. Preferred are water, ethanol, toluene, etc., which are used either singly or as a suitable mixture of two or more species.
Where the intermediates produced in those Processes 1 to 4 include optical isomers, any known methods of obtaining such xe2x80x9coptical isomers of those intermediatesxe2x80x9d are employable herein. For example, the optical isomers may be derived from optically-active compounds, or racemates may be subjected to optical resolution or asymmetric synthesis.
For the xe2x80x9coptical resolutionxe2x80x9d, referred to is the same as the optical resolution to be mentioned hereinafter.
The xe2x80x9casymmetric synthesisxe2x80x9d may be effected in any per se known manner, including, for example, asymmetric reduction, asymmetric oxidation, asymmetric alkylation, etc. These reactions may be attained, for example, according to the methods described in Shin-Jikken Kagaku Koza, 26 (1992), edited by the Chemical Society of Japan and published by Maruzen Co., etc. Of those, preferred is asymmetric reduction.
The xe2x80x9casymmetric reductionxe2x80x9d includes, for example, reduction using asymmetric metal hydrides, asymmetric hydrogenation, etc. Preferred is asymmetric hydrogenation. The xe2x80x9casymmetric hydrogenationxe2x80x9d includes, for example, a reaction using asymmetric metal catalysts. One embodiment of the asymmetric hydrogenation is effected in the presence of transition metal/optically-active phosphine complexes.
For example, compounds (III), (IV), (V), (VI), (VII), (XVI) and (XVII) produced in any of Processes 1 to 4, wherein each Ring B is a ring of the formula: 
wherein Zb has the same meaning as Z, are subjected to asymmetric hydrogenation to obtain the corresponding optical isomers, respectively. 
In those formulae, * indicates the position of the asymmetric carbon, and the other symbols have the same meanings as above.
As one example of the xe2x80x9casymmetric hydrogenationxe2x80x9d, mentioned is a method of reacting compound (IIIb), (IVb), (Vb), (VIb), (VIIb), (XVIb) or (XVIIb) with approximately 0.00001 to 1 equivalent, preferably approximately 0.001 to 0.1 equivalents of a transition metal/optically-active phosphine complex, in an inert solvent, at room temperature to 100xc2x0 C., preferably at about 50 to 80xc2x0 C., under a hydrogen pressure of 5 to 100 kg/cm2, preferably from 50 to 100 kg/cm2, for 1 to 48 hours, preferably for 1 to 6 hours, to obtain compound (IIIc), (IVc), (Vc), (VIc), (VIIc), (XVIc) or (XVIIc), respectively.
The concentration of the compound (IIIb), (IVb), (Vb), (VIb), (VIIb), (XVIb) or (XVIIb) in the reaction system is 1 to 1000 mg/ml, preferably 50 to 300 mg/ml.
If desired, a suitable amount of a Lewis acid (e.g., boron trifluoride-ether complex, aluminum chloride, titanium tetrachloride, cobalt chloride, etc.) or a mineral acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.) may be added to the reaction system.
The xe2x80x9ctransition metalxe2x80x9d of the xe2x80x9ctransition metal/optically-active phosphine complexxe2x80x9d includes, for example, ruthenium, rhodium, iridium, palladium, nickel, etc. Of those, preferred is ruthenium.
The optically-active phosphine of the xe2x80x9ctransition metal/optically-active phosphine complexxe2x80x9d includes two optical isomers of (R) configuration and (S) configuration. Either one of the two optical isomers of (R) configuration and (S) configuration is used for the asymmetric reduction to selectively obtain the intended optical isomer product.
Examples of the xe2x80x9coptically-active phosphinexe2x80x9d are (R)-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl [(R)-(BINAP)], (S)-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl [(S)-(BINAP)], (R)-2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl [(R)-(p-tolyl-BINAP)], (S)-2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl [(S)-(p-tolyl-BINAP)] (see JP-A-61-63690); (R)-2,2xe2x80x2-bis[di-(3,5-dimethylphenyl) phosphino]-1,1xe2x80x2-binaphthyl [(R)-(3,5-xylyl-BINAP)], (S)-2,2xe2x80x2-bis[di-(3,5-dimethylphenyl) phosphino]-1,1xe2x80x2-binaphthyl [(S)-(3,5-xylyl-BINAP)] (see JP-A-3-255090); (R)-2,2xe2x80x2-bis (diphenylphosphino)-5,5xe2x80x2,6,6xe2x80x2,7,7xe2x80x2,8,8xe2x80x2-octahydro-1,1xe2x80x2-binaphthyl [(R)-(H8-BINAP)], (S)-2,2xe2x80x2-bis (diphenylphosphino)-5,5xe2x80x2,6,6xe2x80x2,7,7xe2x80x2,8,8xe2x80x2-octahydro-1,1xe2x80x2-binaphthyl [(S)-(H8-BINAP)] (see JP-A-4-139140), etc.
The above xe2x80x9c(R)xe2x80x9d and xe2x80x9c(S)xe2x80x9d each indicates the absolute configuration in that optically-active phosphine.
The xe2x80x9ctransition metal/optically-active phosphine complexxe2x80x9d may additionally have, as ligands, a halogen (e.g., chloro, etc.), an amine (e.g., triethylamine, etc.), an organic acid (e.g., acetic acid, etc.), a C6-10 aryl (e.g., benzene, etc.), etc.
After having been prepared, the xe2x80x9ctransition metal/optically-active phosphine complexxe2x80x9d may be directly used in the reaction without being isolated or purified.
xe2x80x9cRuthenium/optically-active phosphine complexesxe2x80x9d which are preferred examples of the xe2x80x9ctransition metal/optically-active phosphine complexxe2x80x9d each are composed of ruthenium and either one, optically-active (R)xe2x80x94 or (S)-phosphine compound, and include, for example, the following:
Bis[[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl]]dichlororuthenium]triethylamine (referred to as [RuCl2[(R)xe2x80x94 or (S)-(BINAP)]]2NEt3);
Bis[[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl]]dichlororuthenium]triethylamine (referred to as [RuCl2[(R)xe2x80x94 or (S)-(p-tolyl-BINAP)]]2NEt3);
Bis[[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(di-(3,5-dimethylphenyl) phosphino)-1,1xe2x80x2-binaphthyl]]dichlororuthenium]triethylamine (referred to as [RuCl2[(R)xe2x80x94 or (S)-(3,5-xylyl-BINAP)]]2NEt3);
Bis[[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(diphenylphosphino)-5,5xe2x80x2,6,6xe2x80x2, 7,7xe2x80x2,8,8xe2x80x2-octahydro-1,1xe2x80x2-binaphthyl]]dichlororuthenium]triethylamine (referred to as [RuCl2[(R)xe2x80x94 or (S)xe2x80x94(H8-BINAP)]]2NEt3);
[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl]]ruthenium diacetate (referred to as Ru(CH3CO2)2[(R)xe2x80x94 or (S)xe2x80x94(BINAP)]);
[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl]]ruthenium diacetate (referred to as Ru(CH3CO2)2[(R)xe2x80x94 or (S)-(p-tolyl-BINAP)]);
[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(di-(3,5-dimethylphenyl) phosphino)-1,1xe2x80x2-binaphthyl]]ruthenium diacetate (referred to as Ru(CH3CO2)2[(R)xe2x80x94 or (S)-(3,5-xylyl-BINAP)]);
[(R)xe2x80x94 or (S)-[2,2xe2x80x2-bis(diphenylphosphino)-5,5xe2x80x2, 6,6xe2x80x2,7,7xe2x80x2,8,8xe2x80x2-octahydro-1,1xe2x80x2-binaphthyl]]ruthenium diacetate (referred to as Ru(CH3CO2)2[(R)xe2x80x94 or (S)xe2x80x94(H8-BINAP)]).
The inert solvent includes, for example, hydrocarbons, amides, aromatic solvents, ethers, halogenated hydrocarbons, alcohols, ketones, sulfoxides, nitrites, etc., which may be used either singly or as a suitable mixture of two or more species. Preferred are alcohols, and more preferred is ethanol.
The above xe2x80x9calcoholsxe2x80x9d includes, for example, methanol, ethanol, isopropanol, tert-butanol, etc.
The above xe2x80x9cethersxe2x80x9d includes, for example, ethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, etc.
The above xe2x80x9chalogenated hydrocarbonsxe2x80x9d includes, for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
The above xe2x80x9caromatic solventsxe2x80x9d includes, for example, benzene, toluene, xylene, pyridine, etc.
The above xe2x80x9chydrocarbonsxe2x80x9d includes, for example, hexane, pentane, cyclohexane, etc.
The above xe2x80x9camidesxe2x80x9d includes, for example, N,Nxe2x80x2-dimethylformamide (DMF), N,Nxe2x80x2-dimethylacetamide, N-methylpyrrolidone, etc.
The above xe2x80x9cketonesxe2x80x9d includes, for example, acetone, methyl ethyl ketone, etc.
The above xe2x80x9csulfoxidesxe2x80x9d includes, for example, dimethylsulfoxide (DMSO), etc.
The above xe2x80x9cnitrilesxe2x80x9d includes, for example, acetonitrile, propionitrile, etc.
The above xe2x80x9cestersxe2x80x9d includes, for example, ethyl acetate, etc.
In the above-mentioned reactions where the starting compounds are substituted by any of amino, carboxy, hydroxy or carbonyl, those groups may be protected by ordinary protective groups which are generally used in peptide chemistry. The protective groups may be removed after the reaction to give the intended products.
The amino-protecting group includes, for example, formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C1-6 alkyloxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), benzoyl, C7-10 aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), C7-14 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The carboxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C7-11 aralkyl (e.g., benzyl, etc.), phenyl, trityl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), a C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The hydroxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C7-10 aralkyl (e.g., benzyl, etc.), formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), benzoyl, C7-10 aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkyl (e.g., methyl, ethyl, propyl, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The carbonyl-protecting group includes, for example, cyclic acetals (e.g., 1,3-dioxorane, etc.), acyclic acetals (e.g., di-C1-6 alkylacetals, etc.), etc.
Those protective groups may be removed by any per se known methods, for example, the methods described in Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1980, etc. For example, the method of removing these protective groups, includes the methods using acids, bases, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.; and reduction, etc.
Compound (I) can be isolated and purified by any known procedures, for example, through solvent extraction, ph adjustment, redistribution, crystallization, recrystallization, chromatography, etc. The starting compounds and intermediates and their salts for compound (I) can also be isolated and purified according to the same known procedures as above, but without any isolation procedure, they may be used in the next step while they are in reaction mixtures.
Compound (I) may also be in the form of hydrates or non-hydrates thereof.
Where compound (I) includes optical isomers, stereoisomers, regio isomers and rotational isomers, those are within the scope of compound (I), and can be isolated as their single compound through per se known synthesis or separation. For example, where optical isomers of compound (I) exist, those resolved from their mixtures through optical resolution are within the scope of compound (I).
The optical isomers can be produced in any per se known manner. Concretely, optically active synthetic intermediates or mixtures of racemate of the final product are subjected to ordinary optical resolution to give the corresponding optical isomers.
For the optical resolution, employable are any per se known methods, such as a fractional recrystallization method, a chiral column method, a diastereomer method, etc.
1) Fractional Recrystallization
The method which comprises allowing a racemate to react with an optically active compound (e.g., (+)-mandelic acid, (xe2x88x92)-mandelic acid, (+)-tartaric acid, (xe2x88x92)-tartaric acid, (+)-1-phenethylamine, (xe2x88x92)-1-phenethylamine, cinchonine, (xe2x88x92)-cinchonidine, brucine, etc.) to give a salt, which is then isolated through fractional recrystallization, followed by, when desired, subjecting the isolated compound to neutralization to obtain free optical isomers.
2) Chiral Column Method
The method of separating a racemate or a salt thereof, which comprises utilizing a column for fractionating optical isomers (chiral column). In the case of liquid column chromatography, for example, a mixture of optical isomers is applied to a chiral column, such as ENANTIO-OVM (manufactured by Tosoh Corp.), CHIRAL SERIES (manufactured by Daicel Co.), etc., which is then eluted with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.), singly or a suitable mixture of them, to isolate the individual optical isomers. In case of gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science Co.), etc. is used for the fractionation.
3) Diastereomer Method
A racemic mixture is chemically reacted with an optically-active reagent to give a mixture of diastereomer, which is subjected to ordinary separation (e.g., fractional recrystallization, chromatography, etc.) to give single compounds. The thus-isolated single compounds are then chemically processed, for example, through hydrolysis to thereby remove the optically-active reagent site from the compounds to obtain optical isomers. For example, where compound (I) has a hydroxy group or a primary or secondary amino group in the molecule, it is condensed with an optically-active organic acid (e.g., MPTA [xcex1-methoxy-xcex1-(trifluoromethyl) phenyl-acetic acid], (xe2x88x92)-menthoxyacetic acid, etc.) or the like to give the corresponding ester-type or amide-type diastereomer. On the other hand, where compound (I) has a carboxylic acid group, it is condensed with an optically-active amine or alcohol reagent to give the corresponding amide-type or ester-type diastereomer. The thus-isolated diastereomer is then subjected to acidic or basic hydrolysis, through which it is converted into the optical isomer of the original compound.
In the above-mentioned reactions, an optical isomer of the compound of the formula: 
wherein R1b and R2b each represents methyl or ethyl, k represents 1 or 2, and * indicates the position of the asymmetric carbon, or a salt thereof is a novel compound.
Compound (I) of the present invention has both an excellent inhibitory effect on amyloid-xcex2 protein production and/or secretion and an excellent stimulating effect on secreted form of amyloid precursor protein (sAPP) secretion, and thus is effective in preventing and/or treating neurodegenerative disorders, amyloid angiopathy, neurological disorders caused by cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, etc. Compound (Ixe2x80x2) also has the inhibitory effect on amyloid-xcex2 protein production and/or secretion and stimulating effect on sAPP secretion.
In addition, compounds (I) and (Ixe2x80x2) have low toxicity. For example, in the experiment of acute toxicity, no mouse was dead by the oral administration of the compound obtained in Example 12 mentioned below a dose of more than 1000 mg/kg. Moreover, compounds (I) and (Ixe2x80x2) easily penetrate into the brain following the oral administration.
Therefor, compounds (I) and (Ixe2x80x2) are useful as safe medicines for preventing and/or treating neurodegenerative disorders, amyloid angiopathy, neurological disorders caused by cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, in mammals including human beings. They are also useful in ameliorating derangements (for example, depression, anxiety, compulsive neurosis, sleep disorders, etc.) caused by neurodegenerative disorders or neurological disorders. Of those, compounds (I) and (Ixe2x80x2) are preferably effective for neurodegenerative disorders such as Alzheimer""s disease, Down""s syndrome, senile dementia, Parkinson""s disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus of spinal, diabetic neuropathy, Huntington""s disease, multiple sclerosis, etc. Among others, preferred is neurodegenerative disorders to be coursed by amyloid-xcex2 protein (e.g., Alzheimer""s disease, Down""s syndrome, etc.), more preferred is Alzheimer""s disease.
Compounds (I) and (Ixe2x80x2) may be used in combination with anti-dementia drugs (e.g., acetylcholinesterase inhibitor, etc.), and so forth.
Compounds (I) and (Ixe2x80x2) can be formulated into pharmaceutical compositions by any per se known means. Directly or after having been formulated into pharmaceutical compositions along with suitable amounts of any pharmaceutically acceptable carriers, compounds (I) and (Ixe2x80x2) can be safely administered to mammals including human beings. For example, compound (I) or (Ixe2x80x2) can be mixed with suitable amounts of any desired, pharmaceutically-acceptable carriers in any per se known formulation processes to give tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained release preparations, etc., which may be safely administered to mammals including human beings, either orally or non-orally (for example, topically, rectally, intravenously, etc.).
In the pharmaceutical composition of the present invention, the amount of compound (I) or (Ixe2x80x2) is 0.1 to 100% by weight of the total weight of the composition. The dose of the composition varies depending on the subject to which the composition is administered, the administration route employed, the disorder of the subject, etc. For example, for the peroral composition for treating Alzheimer""s disease, its dose may be about 0.1 to 500 mg/adult (weighing about 60 kg) or so, preferably about 1 to 100 mg/adult or so, more preferably 5 to 100 mg/adult or so, in terms of the active ingredient [compound (I) or (Ixe2x80x2)], and this may be administered once or several times a day.
Any ordinary organic and inorganic carrier substances that are generally used in formulating medicines are usable as the carriers for formulating the pharmaceutical compositions of the present invention. For example, employable are ordinary excipients, lubricants, binders, disintegrators, etc. for formulating solid preparations; and solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents, etc. for formulating liquid preparations. If desired, further employable are other additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, etc.
The excipients include, for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, etc.
The lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
The binders include, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc.
The disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
The solvents include, for example, water for injections, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.
The solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
The suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.
The isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.
The buffers include, for example, liquid buffers of phosphates, acetates, carbonates, citrates, etc.
The soothing agents include, for example, benzyl alcohol, etc.
The preservatives include, for example, parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
The antioxidants include, for example, sulfites, ascorbic acid, etc.
The invention will be described in more detail hereinunder, with reference to Reference Examples, Examples, and Test Examples, which, however, are to concretely demonstrate the invention but not to restrict the scope of the invention. Various changes and modifications can be made within the range that does not deviate the scope of the invention.
xe2x80x9cRoom temperaturexe2x80x9d as referred to in the following Reference Examples and Examples is meant to indicate a temperature falling between 0xc2x0 C. and 30xc2x0 C. For removing water from the organic solution used therein, employed were anhydrous magnesium sulfate or anhydrous sodium sulfate. Unless otherwise specifically indicated, xe2x80x9c%xe2x80x9d is by weight.
The IR absorption spectra mentioned below were measured in a diffused reflection method using a Fourier transform infrared spectrophotometer.
The meanings of the abbreviations used hereinunder are as follows:
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl3: deuterated chloroform
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
1H NMR: proton nuclear magnetic resonance spectrum (generally measured as the free form of each sample in CDCl3)
IR: infrared absorption spectrum
N-(6-Methoxy-1-oxo-2-tetralinyl)methyl-N,N,N-trimethylammonium iodide (1.137 g), piperidine (0.36 ml) and triethylamine (0.55 ml) were added to acetonitrile (300 ml). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated. Water was added to this, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate/hexane=1/2), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate. The resulting hydrochloride was recrystallized from methanol-ethyl acetate to obtain the entitled compound (0.586 g).
m.p.: 182-183xc2x0 C.
Compounds of the following Reference Examples 2 and 3 were obtained in the same manner as in Reference Example 1
m.p.: 166-169xc2x0 C.
Solvent for recrystallization: methanol-ethyl acetate
m.p.: 91-92xc2x0 C.
Solvent for recrystallization: ethyl acetate-diisopropyl ether
1 N Sodium hydroxide was added to 2-(N,N-dimethylamino) methyl-7-methoxy-1-tetralone hydrochloride (8.46 g) to convert it into a free compound, which was extracted with ethyl acetate. The extract was dried, and then concentrated. Sodium borohydride (2.32 g) was added to a methanol solution (150 ml) of the resulting residue, with cooling with ice, which was then stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was concentrated under reduced pressure, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. Concentrated hydrochloric acid (6.4 g) and 10% palladium-carbon (0.7 g) were added to an ethanol solution (100 ml) of the resulting residue, which was thus catalytically reduced under a hydrogen pressure of 5 atmospheres at 60xc2x0 C. for 8 hours. The catalyst was removed from the reaction mixture through filtration, and the filtrate was concentrated. The residue was recrystallized from methanol-ethyl acetate to obtain the entitled compound (6.53 g).
m.p.: 212-213xc2x0 C.
Compounds of the following Reference Examples 5 to 7 were obtained in the same manner as in Reference Example 4.
m.p.: 197-199xc2x0 C.
Solvent for recrystallization: methanol-ethyl acetate
m.p.: 174-177xc2x0 C.
Solvent for recrystallization: methanol-diethyl ether
m.p.: 215-216xc2x0 C.
Solvent for recrystallization: methanol-diethyl ether
p-Toluenesulfonyl chloride (2.06 g) was added to an acetonitrile solution (20 ml) of 2-hydroxymethyl-6-methoxytetralin (1.888 g; described in J. Med. Chem., Vol. 37, p. 526, 1994) and pyridine (4.0 ml), with cooling with ice. The reaction mixture was stirred at room temperature for 24 hours, and 1 N hydrochloric acid was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. Sodium iodide (2.20 g) was added to an acetone solution (30 ml) of the resulting residue. The reaction mixture was heated under reflux for 16 hours, and then concentrated. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/2) to obtain the entitled compound (2.506 g).
1H NMR xcex4: 1.38-1.60(1H,m), 1.80-2.11(2H,m), 2.45(1H,dd,J=16 Hz,8 Hz), 2.76-3.00(3H,m), 3,26(2H,d,J=6 Hz), 3.77(3H,s), 6.60-6.74(2H,m), 7.00(1H,d,J=8 Hz).
2-Iodomethyl-6-methoxytetralin (0.918 g; obtained in Reference Example 8), dipropylamine (0.83 ml) and potassium carbonate (0.90 g) were added to DMF (15 ml). The reaction mixture was stirred at room temperature for 20 hours. Water was added to this, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to obtain its hydrochloride. This was recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (0.409 g).
m.p.: 135-137xc2x0 C.
An acetonitrile (400 ml) solution of N-(6-methoxy-1-oxo-2-tetralinyl) methyl-N,N,N-trimethylammonium iodide (44.5 g), N-benzyl-N-methylamine (14.4 g) and triethylamine (18 ml) was heated under reflux for 16 hours. The reaction mixture was concentrated, then water (200 ml) was added to the resulting residue, and an aqueous solution of 1 N sodium hydroxide was added to this to make it have pH of 9, which was then extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried, and then concentrated. The residue was dissolved in methanol, and sodium borohydride (7.1 g) was added thereto, with cooling with ice, and then stirred at room temperature for 16 hours. The reaction mixture was concentrated, then water (200 ml) was added to the resulting residue, and an aqueous solution of 1 N sodium hydroxide was added to this to make it have pH of 9, which was then extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried and then concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/1). Concentrated hydrochloric acid (26 ml) and 10% palladium-carbon (3 g) were added to an ethanol solution (200 ml) of the effective fraction obtained through the chromatography. The reaction mixture was catalytically reduced under atmospheric hydrogen pressure for 48 hours. The catalyst was removed from the mixture through filtration, and the resulting filtrate was concentrated. The crystals formed were washed with acetone to obtain the entitled compound (8.17 g).
m.p.: 192-193xc2x0 C.
The entitled compound was obtained in the same manner as in Reference Example 10.
m.p. 217-218xc2x0 C.
Solvent for recrystallization: ethanol-diisopropyl ether
Acetyl chloride (0.67 g) was added to a pyridine solution (15 ml) of 2-aminomethyl-6-methoxytetralin hydrochloride (1.5 g; obtained in Reference Example 11), and the reaction mixture was stirred at room temperature for 16 hours, to which was added ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (960 mg).
m.p.: 96-97xc2x0 C.
(6-Methoxy-2-tetralin)acetic acid (1.491 g), dimethylamine hydrochloride (0.846 g), WSC (1.726 g), 1-hydroxybenzotriazole (1.069 g) and triethylamine (2.8 ml) were added to acetonitrile (30 ml). The reaction mixture was stirred at room temperature for 20 hours, and 1 N hydrochloric acid was added thereto, which was then extracted with ethyl acetate. The organic layer was separated, washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain the entitled compound (1.667 g).
1H NMR xcex4: 1.34-1.57(1H,m), 1.91-2.08(1H,m), 2.22-2.51(2H,m), 2.36(2H,s), 2.77-2.94(3H,m),2.98(3H,s), 3.02(3H,s), 3.77(3H,s), 6.59-6.72(2H,m), 6.96(1H,d,J=8 Hz).
Lithium aluminum hydride (0.25 g) was added to a THF solution (20 ml) of N,N-dimethyl-(6-methoxy-2-tetralin) acetamide (1.613 g; obtained in Reference Example 13). The reaction mixture was stirred at room temperature for 6 hours, to which was added water. Insoluble substances were removed from the reaction mixture through filtration, and the filtrate was concentrated. The residue was processed with a solution of 4 N hydrochloric acid-ethyl acetate to obtain its hydrochloride, which was then recrystallized from methanol-ethyl acetate to obtain the entitled compound (1.247 g).
m.p.: 183-185xc2x0 C.
2-(N-benzylamino)methyl-6-methoxytetralin hydrochloride (0.602 g; obtained in Reference Example 6), 3,3-diphenylpropyl iodide (0.803 g) and potassium carbonate (0.800 g) were added to DMF (20 ml). The reaction mixture was stirred at room temperature for 24 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain the entitled compound (0.335 g).
1H NMR xcex4: 1.11-1.40(1H,m), 1.70-2.05(2H,m), 2.13-2.48(7H,m), 2.62-2.88(3H,m), 3.54(2H,s), 3.76(3H,s), 3.98(1H,t,J=8 Hz), 6.55-6.70(2H,m), 6.95(1H,d,J=8 Hz), 7.04-7.38(15H,m).
2-(N,N-Dimethylamino)methyl-6-methoxytetralin hydrochloride (0.365 g; obtained in Reference Example 5) was added to 48% hydrobromic acid (10 ml), and the reaction mixture was heated under reflux for 3 hours, and then left cooled. This was neutralized with an aqueous solution of 1 N sodium hydroxide, and a solution of 10% potassium carbonate was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/2), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to obtain its hydrochloride. This was washed with ethyl acetate to obtain the entitled compound (0.211 g).
m.p.: 221-224xc2x0 C.
Compounds of the following Reference Examples 17 to 22 were obtained in the same manner as in Reference Example 16.
m.p.: 173-175xc2x0 C.
Solvent for recrystallization: methanol-diisopropyl ether
1H NMR xcex4: 1.10-1.34(1H,m), 1.68-2.02(2H,m), 2.12-2.48(7H,m), 2.57-2.87(3H,m), 3.55(2H,d,J=2 Hz), 3.98(1H,t,J=8 Hz), 6.48-6.60(2H,m), 6.89(1H,d,J=8 Hz), 7.04-7.34(15H,m).
m.p.: 216-218xc2x0 C.
Solvent for recrystallization: methanol-diethyl ether
m.p.: 114-116xc2x0 C.
Solvent for recrystallization: ethyl acetate-hexane
m.p.: 197-198xc2x0 C.
Solvent for recrystallization: methanol-ethyl acetate
m.p.: 229-230xc2x0 C.
Solvent for recrystallization: methanol-ethyl acetate
Boron tribromide (1.57 g) was added to a methylene chloride (15 ml) solution of N-(6-methoxy-2-tetralinyl) methylacetamide (730 mg; obtained in Reference Example 12), at 0xc2x0 C. The reaction mixture was warmed to room temperature, and stirred for 1 hour. Water was added to this, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous potassium carbonate solution, then dried, and concentrated. The residue was dissolved in DMF (20 ml), to which were added 4-(iodomethyl)biphenyl (1.35 g) and potassium carbonate (1.36 g). The reaction mixture was stirred at room temperature for 16 hours. Water was added to this, which was then extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1). The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (750 mg).
m.p.: 144-145xc2x0 C.
(6-Methoxy-2-tetralin)acetic acid (15.22 g) was added to 48% hydrobromic acid (100 ml), and the reaction mixture was heated under reflux for 3 hours. After this was cooled, water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting residue was dissolved in methanol (200 ml), to which was dropwise added thionyl chloride (6.0 ml) at 0xc2x0 C. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (9.566 g).
1H NMR xcex4: 1.32-1.55(1H,m), 1.84-2.00(1H,m), 2.10-2.48(4H,m), 2.70-2.89(3H,m), 3.71(3H,s), 4.80(1H,s), 6.52-6.64(2H,m), 6.91(1H,d,J=8 Hz).
Methyl (6-hydroxy-2-tetralin)acetate (0.608 g; obtained in Reference Example 24), 2-naphthylmethyl bromide (0.737 g) and potassium carbonate (0.59 g) were added to DMF (20 ml). The reaction mixture was stirred at room temperature for 5 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4), and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (0.624 g).
m.p.: 73-75xc2x0 C.
Lithium aluminum hydride (75 mg) was added to a THF solution (10 ml) of methyl [6-(2-naphthyl)methoxy-2-tetralin]acetate (0.712 g; obtained in Reference Example 25). The reaction mixture was stirred at room temperature for 2 hours, and then water was added thereto. Insoluble substances were removed from the reaction mixture through filtration, and the filtrate was concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (0.451 g).
m.p.: 90-91xc2x0 C.
P-Toluenesulfonyl chloride (0.301 g) was added to a dichloromethane solution (15 ml) of 2-(2-hydroxyethyl)-6-(2-naphthyl) methoxytetralin (0.712 g; obtained in Reference Example 26) and pyridine (0.19 ml), at 0xc2x0 C. The reaction mixture was stirred at room temperature for 24 hours, and 1 N hydrochloric acid was added thereto, which was then extracted with dichloromethane. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was dissolved in acetone (10 ml), to which was added sodium iodide (0.371 g). The reaction mixture was heated under reflux for 4 hours, and then concentrated. A saturated aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were added to this, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (0.451 g).
1H NMR xcex4: 1.30-1.60(1H,m), 1.75-2.02(4H,m), 2.26-2.46(1H,m), 2.72-2.89(3H,m), 3.30(2H,t,J=7 Hz), 5.19(2H,s), 6.72-6.83(2H,m), 6.98(1H,d,J=8 Hz), 7.42-7.57 (3H,m), 7.78-7.91(4H,m).
60% oily sodium hydride (1.034 g) was added to a DMF solution (100 ml) of methyl (6-hydroxy-2-tetralin) acetate (4.407 g; obtained in Reference Example 24), at 0xc2x0 C. The reaction mixture was stirred at 40xc2x0 C. for 1 hour, and then again cooled to 0xc2x0 C., to which was then added 4-(chloromethyl)biphenyl (4.466 g). The reaction mixture was stirred at room temperature for 14 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were washed with diisopropyl ether to obtain the entitled compound (3.995 g).
m.p.: 65-70xc2x0 C.
Methyl [6-(4-biphenylyl)methoxy-2-tetralinlacetate (3.480 g; obtained in Reference Example 28) was dissolved in THF (80 ml) and methanol (40 ml), to which was added an aqueous solution of 1 N sodium hydroxide (20 ml). The reaction mixture was stirred at room temperature for 7 hours, and then concentrated. 1 N hydrochloric acid was added to the residue until the resulting mixture became acidic, and this was then extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from THF-diisopropyl ether to obtain the entitled compound (2.956 g).
m.p.: 167-169xc2x0 C.
[6-(4-Biphenylyl)methoxy-2-tetralin]acetic acid (1.866 g; obtained in Reference Example 29), dimethylamine hydrochloride (0.553 g), WSC (1.512 g), 1-hydroxybenzotriazole (0.764 g) and triethylamine (2.1 ml) were added to a mixture of acetonitrile (50 ml) and THF (50 ml). The reaction mixture was stirred at room temperature for 20 hours, and 1 N hydrochloric acid was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.497 g).
m.p.: 114-119xc2x0 C.
A THF solution (40 ml) of 6-acetylamino-1-tetralone (1.692 g) was added to an acetonitrile solution (40 ml) of N,N-dimethylmethylene ammonium chloride (2.04 g), then stirred at room temperature for 24 hours, and concentrated. An aqueous solution of 10% potassium carbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was dissolved in methanol (50 ml), to which was added sodium borohydride (0.86 g). The reaction mixture was stirred at room temperature for 1 hour, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was dissolved in methanol (50 ml), to which were added 10% palladium-carbon (0.4 g) and 1 N hydrochloric acid (20 ml). Then, this was catalytically reduced under a hydrogen pressure of 1 atmosphere, for 12 hours. The palladium-carbon was removed from the reaction mixture through filtration, the filtrate was concentrated, and an aqueous solution of 10% potassium carbonate was added thereto to form a free form compound. Then, this was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.862 g).
m.p.: 104-107xc2x0 C.
6-Acetylamino-2-(N,N-dimethylamino)methyltetralin hydrochloride (0.879 g; obtained in Reference Example 31) was added to 2 N hydrochloric acid. The reaction mixture was heated under reflux for 90 minutes, and then an aqueous solution of 1 N sodium hydroxide was added thereto to thereby make the resulting mixture have pH of 9. Then, this was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain the entitled compound (0.231 g).
1H NMR xcex4: 1.24-1.47(1H,m), 1.60-2.00(3H,m), 2.13-2.40(2H,m), 2.24(6H,s), 2.66-2.89(3H,m), 3.23-2.73(2H,br), 6.42-6.52(2H,m), 6.89(1H,d,J=8 Hz).
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (5.0 g; obtained in Reference Example 16) was dissolved in DMF (130 ml), to which was added 60% oily sodium hydride (1.46 g) at 0xc2x0 C. The reaction mixture was warmed to room temperature, and stirred for 1 hour. This was again cooled to 0xc2x0 C., to which was added a DMF solution (20 ml) of 4-bromobenzyl bromide (10.0 g). The reaction mixture was stirred at room temperature for 2 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (3.4 g).
1H NMR xcex4: 1.2-1.5(1H,m), 1.7-2.1(2H,m), 2.1-2.5(3H,m), 2.24(6H,s), 2.7-3.0(3H,m), 4.97(2H,s), 6.6-6.8(2H,m), 7.00(1H,d,J=8 Hz), 7.28(2H,d,J=8 Hz), 7.50(2H,d,J=8 Hz).
Compounds of the following Reference Examples 34 to 40 were obtained in the same manner as in Reference Example 33.
1H NMR xcex4: 1.2-1.5(1H,m), 1.7-2.1(2H,m), 2.1-2.5(3H,m), 2.24(6H,s), 2.7-3.0(3H,m), 4.99(2H,s), 6.6-6.8(2H,m), 7.01(1H,d,J=8 Hz), 7.1-7.5(3H,m), 7.59(1H,s).
1H NMR xcex4: 1.2-1.5(1H,m), 1.7-2.1(2H,m), 2.1-2.5(3H,m), 2.24(6H,s), 2.7-3.0(3H,m), 5.09(2H,s), 6.7-6.8(2H,m), 7.02(1H,d,J=8 Hz), 7.17(1H,td,J=7 Hz,2 Hz), 7.32(1H,td,J=7 Hz,2 Hz), 7.5-7.6(2H,m).
m.p.: 196-198xc2x0 C.
Solvent for recrystallization: methanol-ethyl acetate
m.p.: 203-207xc2x0 C.
Solvent for recrystallization: methanol-diethyl ether
m.p.: 217-218xc2x0 C.
Solvent for recrystallization: methylene chloride-diethyl ether
m.p.: 208-209xc2x0 C.
Solvent for recrystallization: ethanol-ethyl acetate
This was amorphous powder.
1H NMR xcex4: 1.12-1.35(1H,m), 1.72-2.06(2H,m), 2.14-2.48(7H,m), 2.54-2.88(3H,m), 3.55(2H,d,J=2 Hz), 3.98(1H,t,J=7 Hz), 5.07(2H,s), 6.63-6.74(2H,m), 6.96(1H,d,J=8 Hz), 7.06-7.34(15H,m), 7.37-7.53(3H,m).
IR (KBr): 3058, 3028, 2925, 2572, 1592, 1500, 1234, 747, 701 cmxe2x88x921.
Methyl (6-hydroxy-2-tetralin)acetate (17.5 g), 4-bromobenzyl bromide (24.0 g) and potassium carbonate (30.6 g) were added to DMF (160 ml). The reaction mixture was stirred at room temperature for 12 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from toluene-diisopropyl ether to obtain the entitled compound (31.0 g).
m.p.: 78-79xc2x0 C.
Methyl [6-(4-bromobenzyl)oxy-2-tetralin]acetate (31.0 g) was dissolved in methanol (200 ml), to which was added an aqueous solution of 1 N sodium hydroxide (200 ml). The reaction mixture was stirred at 80xc2x0 C. for 4 hours, and then concentrated. 1 N hydrochloric acid was added to the residue until the resulting mixture became acidic, and this was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (29.4 g).
m.p.: 145-146xc2x0 C.
A 28% sodium methoxide-methanol solution (17.3 g) was added to a methanol solution (100 ml) of methyl (6-methoxy-1-oxo-2-tetralin)carboxylate (21 g; described in J. Am. Chem. Soc., Vol. 78, p. 461, 1951). To the reaction mixture was added a methanol solution (100 ml) of methyl acrylate (9.7 ml), and stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous solution of 10% citric acid, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (19.7 g).
m.p.: 66-67xc2x0 C.
6 N Hydrochloric acid (150 ml) was added to an acetic acid solution (30 ml) of methyl 3-(6-methoxy-2-methoxycarbonyl-1-oxo-2-tetralin) propionate (17.7g), and heated under reflux for 2 hours. Water (200 ml) was added to the reaction mixture, and the crystals formed were taken out through filtration to obtain the entitled compound (13.3 g).
m.p.: 129-130xc2x0 C.
Methyl 3-(6-methoxy-1-oxo-2-tetralin)carboxylate (20 g), ethyl 4-bromocrotonate (26.4 g) and potassium carbonate (23.6 g) were added to DMF (300 ml). The reaction mixture was stirred at 80xc2x0 C. for 12 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. 10% palladium-carbon (3.0 g) was added to an ethanol solution (200 ml) of the residue, which was thus catalytically reduced under a hydrogen pressure of one atmosphere at room temperature for 12 hours. The catalyst was removed from the reaction mixture through filtration, and the filtrate was concentrated. 6 N hydrochloric acid (100 ml) was added to an acetic acid solution (50 ml) of the residue, and heated under reflux for 4 hours. Water (200 ml) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (14.0 g).
m.p.: 91-92xc2x0 C.
Perchloric acid (0.25 ml) and 10% palladium-carbon (1.0 g) were added to an acetic acid solution (50 ml) of 3-(6-methoxy-1-oxo-2-tetralin)propionic acid (10 g), which was thus catalytically reduced under a hydrogen pressure of one atmosphere at room temperature for 24 hours. The catalyst was removed from the reaction mixture through filtration, and the filtrate was concentrated. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from toluene-diisopropyl ether to obtain the entitled compound (6.6 g).
m.p.: 114-115xc2x0 C.
The entitled compound was obtained in the same manner as in Reference Example 46.
m.p.: 100-101xc2x0 C.
Solvent for recrystallization: toluene-diisopropyl ether
[6-(4-Bromobenzyl)oxy-2-tetralin]acetic acid (15.0 g), dimethylamine hydrochloride (4.24 g), WSC (12.0 g), 1-hydroxybenzotriazole (6.13 g) and triethylamine (16.7 ml) were added to a mixed solvent of acetonitrile (200 ml) and THF (200 ml). The reaction mixture was stirred at room temperature for 12 hours, and 1 N hydrochloric acid was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (14.3 g).
m.p.: 86-87xc2x0 C.
Compounds of the following Reference Examples 49 and 50 were obtained in the same manner as in Reference Example 48.
This was oily.
1H NMR xcex4: 1.32-1.54(1H,m), 1.60-1.84(3H,m), 1.84-2.02(1H,m),2.26-2.50(3H,m), 2.70-2.90(3H,m), 2.95(3H,s),3.03(3H,s), 3.76(3H,s), 6.56-6.72(2H,m), 6.97(1H,d,J=8 Hz).
This was oily.
1H NMR xcex4: 1.30-1.50(3H,m), 1.60-1.84(3H,m), 1.84-2.00(1H,m), 2.24-2.44(3H,m), 2.70-2.90(3H,m), 2.95(3H,s), 3.01(3H,s), 3.76(3H,s), 6.56-6.72(2H,m), 6.97(1H,d,J=8 Hz).
Lithium aluminum hydride (1.95 g) was added to a THF solution (300 ml) of [6-(4-bromobenzyl)oxy-2-tetralin]-N,N-dimethylacetamide (13.8 g). The reaction mixture was stirred at room temperature for 2 hours, and then an aqueous solution of 1 N sodium hydroxide was added thereto. Insoluble substances were removed from the reaction mixture through filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate to methanol), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-ethyl acetate to obtain the entitled compound (10.5 g).
m.p.: 200-202xc2x0 C.
Compounds of the following Reference Examples 52 and 53 were obtained in the same manner as in Reference Example 51.
m.p.: 163-164xc2x0 C.
Solvent for recrystallization: methanol-diisopropyl ether
m.p.: 144-145xc2x0 C.
Solvent for recrystallization: methanol-diisopropyl ether
2-[3-(N,N-Dimethylamino)propyl]-6-methoxytetralin hydrochloride (3.6 g) was added to 48% hydrobromic acid (20 ml), and the reaction mixture was heated under reflux for 3 hours, and then left cooled. This was neutralized with an aqueous solution of 1 N sodium hydroxide, and an aqueous solution of 10% potassium carbonate was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (2.0 g).
m.p.: 110-111xc2x0 C.
The entitled compound was obtained in the same manner as in Reference Example 54.
m.p.: 123-124xc2x0 C.
Solvent for recrystallization: methanol-diisopropyl ether
Dimethylamine hydrochloride (24.3 g, 298 mmols), WSC (66.0 g, 344 mmols) and 1-hydroxybenzotriazole hydrate (35.1 g, 230 mmols) were added to an acetonitrile solution (1 liter) of (6-methoxy-1-oxo-2-tetralin) acetic acid (53.8 g, 230 mmols; described in Eur. J. Med. Chem., Vol. 25, p. 765, 1990). Triethylamine (96 ml, 689 mmols) was added to the reaction mixture with cooling with ice, and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-toluene to obtain the entitled compound (34 g).
m.p.: 102-104xc2x0 C.
Sodium borohydride (15 g, 397 mmols) was divided into 3 portions, which were separately added to a methanol solution (1 liter) of N,N-dimethyl-(6-methoxy-1-oxo-2-tetralin) acetamide (44.7 g, 180 mmols) with cooling with ice. The reaction mixture was stirred at room temperature for 2 hours, then neutralized with 1 N hydrochloric acid, and concentrated under reduced pressure to about ⅓. Water was added to the concentrate, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated under reduced pressure. P-toluenesulfonic acid hydrate (700 mg, 4.06 mmols) was added to a toluene solution (700 ml) of the resulting residue, and heated under reflux for 30 minutes. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to ethyl acetate alone) to obtain the entitled compound (37.5 g).
1H NMR xcex4: 2.30(2H,t,J=8.0 Hz), 2.83(2H,t,J=8.0 Hz), 2.99(3H,s), 3.04(3H,s), 3.26(2H,s), 3.79(3H,s), 6.21(1H,s), 6.62-6.72(2H,m),6.86-6.96(1H,m).
Degassed ethanol (160 ml) was added to N,N-dimethyl-[6-methoxy-2-(3,4-dihydronaphthalene)]acetamide (18.03 g, 73.50 mmols) and [RuCl2[(R)-(BINAP)]]2NEt3 (1.24 g, 0.734 mmols), and the resulting solution was transferred into an autoclave, in which the solution was stirred under a hydrogen pressure of 100 kg/cm2, at 70xc2x0 C. for 6 hours. This was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=1/2) to obtain the entitled compound (15.5 g, 98.3% e.e.).
m.p.: 70-71xc2x0 C.
Solvent for recrystallization: ethyl acetate-hexane
[xcex1]D25=xe2x88x9261.3xc2x0 (c=1.00, chloroform)
Elemental Analysis: for C15H21NO2 
Degassed ethanol (160 ml) was added to N,N-dimethyl-[6-methoxy-2-(3,4-dihydronaphthalene)]acetamide (18.06 g, 73.50 mmols) and [RuCl2[(S)-(BINAP)]]2NEt3 (1.24 g, 0.734 mmols), and the resulting solution was transferred into an autoclave, in which the solution was stirred under a hydrogen pressure of 100 kg/cm2, at 70xc2x0 C. for 6 hours. This was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=1/2) to obtain the entitled compound (15.8 g, 98.7% e.e.).
m.p.: 71-72xc2x0 C.
Solvent for recrystallization: ethyl acetate-hexane
[xcex1]D25=+63.70 (c=1.00, chloroform)
Elemental Analysis: for C15H21NO2 
Lithium aluminum hydride (0.203 g) was added to a THF solution (15 ml) of (+)-N,N-dimethyl-(6-methoxy-2-tetralin) acetamide (0.870 g). The reaction mixture was stirred at room temperature for 50 minutes, then heated under reflux for 30 minutes, and thereafter left cooled. Water was added to this, from which were removed insoluble substances through filtration, and the filtrate was then concentrated. The residue was purified by alumina column chromatography (eluent:hexane alone to ethyl acetate/hexane=1/10 to 1/4), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate solution to form a hydrochloride. The thus-formed salt was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (0.749 g).
m.p.: 195-197xc2x0 C.
[xcex1]D20=+68.2xc2x0 (c=0.55, methanol)
(+)-2-[2-(N,N-Dimethylamino)ethyl]-6-methoxytetralin hydrochloride (0.602 g) was added to 48% hydrobromic acid (10 ml), and the reaction mixture was heated under reflux for 3.5 hours, and then left cooled. This was neutralized with an aqueous solution of 1 N sodium hydroxide, and a solution of 10% potassium carbonate was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (0.490 g).
m.p.: 213-215xc2x0 C.
[xcex1]D20=+69.1xc2x0 (c=0.52, methanol)
Lithium aluminum hydride (0.130 g) was added to a THF solution (15 ml) of (xe2x88x92)-N,N-dimethyl-(6-methoxy-2-tetralin) acetamide (0.807 g). The reaction mixture was stirred at room temperature for 15 minutes, then heated under reflux for 15 minutes, and thereafter left cooled. Water was added to this, from which were removed insoluble substances, and the filtrate was concentrated. The residue was purified by alumina column chromatography (eluent: hexane alone to ethyl acetate/hexane=1/4), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (0.683 g).
m.p.: 193-195xc2x0 C.
[xcex1]D20=xe2x88x9268.0xc2x0 (c=0.49, methanol)
(xe2x88x92)-2-[2-(N,N-Dimethylamino)ethyl]-6-methoxytetralin hydrochloride (0.563 g) was added to 48% hydrobromic acid (10 ml), and the reaction mixture was heated under reflux for 4 hours, and then left cooled. This was neutralized with an aqueous solution of 1 N sodium hydroxide, and a solution of 10% potassium carbonate was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (0.480 g).
m.p.: 213-215xc2x0 C.
[xcex1]D20=xe2x88x9269.9xc2x0 (c=0.55, methanol)
To a suspension of lithium aluminum hydride (4.71 g) in THF (200 ml) was added a solution of methyl 6-(4-biphenylyl) methoxy-2-tetralinacetate (24.0 g) in THF (50 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr and diluted with saturated aqueous Rochelle salt. The precipitate was filtered off and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the titled compound (22.1 g).
m.p.: 101-102xc2x0 C.
To a solution of triphenylphosphine (12.5 g) in THF (200 ml) were successively added imidazole (3.25 g) and iodine (12.1 g). A solution of 6-(4-biphenylyl) methoxy-2-(2-hydroxyethyl)tetralin (13.15 g) in THF (100 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 5 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; toluene) to obtain the titled compound (13.2 g).
1H NMR xcex4: 1.30-1.60 (1H, m), 1.75-2.00 (4H, m), 2.20-2.46 (1H, m), 2.72-2.92 (3H, m), 3.30 (2H, t, J=7 Hz), 5.07 (2H, s), 6.70-6.84 (2H, m), 6.99 (1H, d, J=8 Hz), 7.14-7.66 (9H, m).
To a suspension of (+)-2-[2-(N,N-dimethylamino) ethyl]-6-hydroxytetralin (9.2 g) in toluene (180 ml) was added sodium hydride (60% in oil, 2.0 g). After stirring at 50xc2x0 C. for 30 min, a solution of 4-bromobenzyl chloride (9.7 g) in toluene (45 ml) was added to the reaction mixture, which was heated under reflux for one hr. The reaction mixture was diluted with water and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) and the precipitate was filtered off. The filtrate was concentrated and the residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:50 to 1:4) and converted into its hydrochloride. The crystals were washed with diisopropyl ether to obtain the titled compound (17.0 g).
m.p.: 191-193xc2x0 C.
[xcex1]D20=+44.1xc2x0 (c=0.99 in methanol).
To a solution of (6-methoxy-1-oxo-2-tetralin) acetic acid (30 g) in acetonitrile (500 ml) were added diethylamine (18.7 g), WSC (36.8 g), and 1-hydroxybenzotriazole (19.6 g). The reaction mixture was stirred at room temperature for 2 days and concentrated. The residue was diluted with ethyl acetate and washed with 0.5 N aqueous hydrochloric acid, and saturated aqueous sodium bicarbonate. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=1:1) and further recrystallized from ethyl acetate-diisopropyl ether to obtain the titled compound (26.8 g).
m.p.: 88-89xc2x0 C.
To a solution of N,N-diethyl-(6-methoxy-1-oxo-2-tetralin) acetamide (25 g) in methanol (400 ml) was added sodium borohydride (6.54 g) in an ice bath. After stirring at room temperature for 30 min, the reaction mixture was neutralized by adding 1 N aqueous hydrochloric acid. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in degassed toluene (300 ml) followed by addition of p-toluenesulfonic acid monohydrate (20 mg). The reaction mixture was heated under reflux for 1 hr and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=1:1) to obtain the titled compound (23.1 g).
1H NMR xcex4: 1.10-1.25 (6H, m), 2.31 (2H, t, J=7.6 Hz), 2.82 (2H, t, J=7.6 Hz), 3.23 (2H, s), 3.26-3.48 (4H, m), 3.78(3H, s), 6.22 (1H, s), 6.62-6.72 (2H, m), 6.84-6.96 (1H, m).
N,N-Diethyl-[6-methoxy-2-(3,4-dihydronaphthalene)] acetamide (10.0 g) and Ru2Cl4[(S)-BINAP]2NEt3 (618 mg) were added to degassed ethanol (170 ml). The reaction mixture was stirred under hydrogen (100 kg/cm2) at 70xc2x0 C. for 6 hr in an autoclave. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1) and alumina column chromatography (eluent; hexane: ethyl acetate=4:1) to obtain the titled compound (8.8 g).
[xcex1]D20=+54.0xc2x0 (c=1.000 in methanol).
1H NMR xcex4: 1.00-1.22 (6H, m), 1.30-1.56 (1H, m), 1.88-2.08 (1H, m), 2.20-2.50 (4H, m), 2.70-3.00 (3H, m), 3.26-3.46 (4H, m), 3.77 (3H, s), 6.60-6.75 (2H, m), 6.96 (1H, d, J=8.0 Hz). Optical purity: 94% e.e. (by HPLC analysis).
N,N-Diethyl-[6-methoxy-2-(3,4-dihydronaphthalene)]acetamide (10.0 g) and Ru2Cl4[(R)-BINAP]2NEt3 (618 mg) were added to degassed ethanol(170 ml). The reaction mixture was stirred under hydrogen (100 kg/cm2) at 70xc2x0 C. for 6 hr in an autoclave. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1) and further purified by alumina column chromatography (eluent; hexane: ethyl acetate=4:1) to obtain the titled compound (8.88 g).
[xcex1]D20=xe2x88x9253.0xc2x0 (c=0.799 in methanol).
1H NMR xcex4: 1.00-1.22 (6H, m), 1.30-1.56 (1H, m), 1.88-2.08 (1H, m), 2.20-2.50 (4H, m), 2.70-3.00 (3H, m), 3.26-3.46 (4H, m), 3.77 (3H, s), 6.60-6.75 (2H, m), 6.96 (1H, d, J=8.0 Hz). Optical purity: 93.7% e.e. (by HPLC analysis).
To a solution of (+)-N,N-diethyl-(6-methoxy-2-tetralin) acetamide (8.8 g) in THF (150 ml) was added lithium aluminum hydride (1.45 g). The reaction mixture was stirred at room temperature and diluted with 1 N aqueous sodium hydroxide. The precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by alumina column chromatography (eluent; hexane: ethyl acetate=10:1) and converted into its hydrochloride, which was recrystallized from methanol-diisopropyl ether to obtain the titled compound (5.4 g).
m.p.: 144-145xc2x0 C.
[xcex1]D20=+61.5xc2x0 (c=1.000 in methanol)
The titled compound was obtained by the similar procedure as in Reference Example 71.
m.p.: 144-145xc2x0 C. (recrystallizing solvent: methanol-diisopropyl ether).
[xcex1]D20=xe2x88x9260.8xc2x0 (c=0.055 in methanol).
(+)-2-[2-(N,N-Diethylamino)ethyl]-6-methoxytetralin hydrochloride (5.2 g) was added to 48% hydrobromic acid (10 ml) and the reaction mixture was heated under reflux for 4 hr and cooled. The reaction mixture was neutralized with 1 N aqueous sodium hydroxide followed by addition of 10% aqueous potassium carbonate and extracted with the combined solvent of ethyl acetate and THF (1:1). The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was recrystallized from methanol-diisopropyl ether to obtain the titled compound (4.5 g).
m.p.: 102-104xc2x0 C.
[xcex1]D20=+73.8xc2x0 (c=0.226 in methanol).
The titled compound was synthesized from Reference Example 72, using similar method as in Reference Example 73.
m.p.: 103-104xc2x0 C. (recrystallizing solvent; methanol-diisopropyl ether).
[xcex1]D20=xe2x88x9273.4xc2x0 (c=1.001 in methanol).
To a solution of [6-(4-biphenylyl)methoxy-2-tetralin]acetic acid (999 mg, Reference Example 29) in THF (15 ml) was added oxalyl chloride (0.28 ml) at 0xc2x0 C. Two drops of DMF was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was dissolved in acetonitrile (30 ml) and THF (10 ml) and a solution of N,N,Nxe2x80x2-trimethylethylenediamine (309mg) and triethylamine (0.56 ml) in acetonitrile (5 ml) were added to the reaction mixture at 0xc2x0 C. The reaction mixture was stirred at room temperature for one hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) and converted into its hydrochloride, which was then recrystallized from methanol-diisopropyl ether to obtain the titled compound (1.159 g).
m.p.: 190-194xc2x0 C.
To a solution of [6-(4-biphenylyl)methoxy-2-tetralin]acetic acid (501 mg, Reference Example 29) in THF (15 ml) was added oxalyl chloride (0.13 ml) at 0xc2x0 C. Two drops of DMF was added and the reaction mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated and the residue was dissolved in acetonitrile (20 ml) and a solution of N,N-diethyl-Nxe2x80x2-methylethylenediamine (216 mg) and triethylamine (0.28 ml) in acetonitrile (10 ml) was added at 0xc2x0 C. The reaction mixture was stirred at room temperature for 45 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) and converted into its hydrochloride, which was then recrystallized from ethanol-diisopropyl ether to obtain the titled compound (603 mg).
m.p.: 148-151xc2x0 C.
A mixture of [6-(4-biphenylyl)methoxy-2-tetralin]acetic acid (1.180 g, Reference Example 29), methylamine hydrochloride (0.496 g), 1-hydroxybenzotriazole (0.509 g), WSC (0.719 g), and triethylamine (1.4 ml) in THF (30 ml) and acetonitrile (30 ml) was stirred at room temperature for 10 days. The reaction mixture was diluted with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried and concentrated. The crude crystals were washed with diisopropyl ether to obtain the titled compound (0.947 g).
m.p.: 156-159xc2x0 C.
A mixture of [6-(4-biphenylyl)methoxy-2-tetralin]acetic acid (4.051 g, Reference Example 29), ethylamine hydrochloride (1.143 g), 1-hydroxybenzotriazole (1.647 g), WSC (2.536 g), and triethylamine (4.5 ml) in THF (80 ml) and acetonitrile (80 ml) was stirred at room temperature for one day. The reaction mixture was diluted with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried and concentrated. The crude crystals were washed with diisopropyl ether to obtain the titled compound (4.216 g).
m.p.: 168-172xc2x0 C.
2-Iodomethyl-6-methoxytetralin (1.209 g, Reference Example 8), 1-benzylpiperazine (0.852 g), and potassium carbonate (0.853 g) were added to DMF (15 ml). The reaction mixture was stirred at room temperature for 18 hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) and converted into its dihydrochloride, which was further washed with diethyl ether to obtain the titled compound (1.217 g).
m.p.: 227-230xc2x0 C. (decomposed).
2-(4-Benzylpiperazin-1-yl)methyl-6-methoxytetralin dihydrochloride (0.849 g) was added to conc. hydrochloric acid (20 ml) and the reaction mixture was heated under reflux for 6 hr and cooled. The resulting precipitate was collected and washed with ethanol, methanol, and diethyl ether to obtain the titled compound (0.523 g).
m.p.: 230-236xc2x0 C. (decomposed).
A mixture of 4-methoxy-2-nitrobenzaldehyde (21.3 g, Org. Synth., Vol. V, p-139, 1973), dimethyl malonate (16.5 g), piperidine (2.5 ml), and acetic acid (0.25 ml) in methanol (125 ml) was heated under reflux for 24 hr. The reaction mixture was concentrated, diluted with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane=1:2) to obtain the titled compound (25 g).
1H NMR xcex4: 3.67 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 7.16 (1H, dd, J=8.8, 2.6 Hz), 7.36 (1H, d, J=8.8 Hz), 7.70 (1H, d, J=2.6 Hz), 8.14 (1H, s).
To a solution of dimethyl (4-methoxy-2-nitrophenyl) methylidenemalonate (25 g) in methanol (200 ml) was added sodium borohydride (3.36 g) in an ice bath. After stirring at room temperature for 1 hr, the reaction mixture was neutralized by adding 1 N aqueous hydrochloric acid. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate: hexane=1:4) to obtain the titled compound (19 g).
1H NMR xcex4: 3.44 (2H, d, J=7.2 Hz), 3.71 (6H, s), 3.86 (3H, s), 3.80-4.00 (1H, m), 7.08 (1H, dd, J=10.8, 2.4 Hz), 7.28 (1H, d, J=10.8 Hz), 7.52 (1H, d, J=2.4 Hz).
A solution of dimethyl (4-methoxy-2-nitrobenzyl) malonate (19 g) in ethanol (200 ml) was hydrogenated in the presence of 10% palladium-C (2.0 g) at room temperature under one atmosphere of hydrogen for 24 hr. The reaction mixture was further stirred at 80xc2x0 C. for 24 hr and the catalyst was removed by filtration. The filtrate was concentrated. The residue was dissolved in the combined solvent of THF (250 ml) and methanol (250 ml) and 1 N aqueous sodium hydroxide (126 ml) was added in an ice bath. The reaction mixture was stirred at room temperature for 72 hr and concentrated. The residue was made acidic by adding 1 N aqueous hydrochloric acid and the precipitate was collected by filtration. The crude crystals were washed with acetone to obtain the titled compound (11.7 g).
m.p.: 145-146xc2x0 C. (decomposed).
To a solution of 1,2,3,4-tetrahydro-7-methoxy-2-oxo-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), 1-hydroxybenzotriazole (2.85 g), and triethylamine (8.5 g) in acetonitrile (400 ml) was added WSC (6.5 g). The reaction mixture was stirred at room temperature for 24 hr and concentrated. The residue was diluted with ethyl acetate and the organic layer was washed with 1 N aqueous hydrochloric acid, 10% aqueous potassium carbonate, and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (1.63 g).
m.p.: 209-210xc2x0 C.
To a solution of 1,2,3,4-tetrahydro-7-methoxy-N,N-dimethyl-2-oxo-3-quinolinecarboxamide (1.63 g) in THF (100 ml) was added 1M borane-THF complex (60 ml). The reaction mixture was heated under reflux for 24 hr. The reaction mixture was concentrated and the residue was heated under reflux with 6 N aqueous hydrochloric acid (30 ml) for 4 hr. The reaction mixture was made basic by adding 6 N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate, saturated aqueous sodium chloride, dried, and concentrated. The residue was converted into its dihydrochloride, which was then recrystallized from methanol-diisopropyl ether to obtain the titled compound (1.27 g).
m.p.: 150-151xc2x0 C.
A solution of 3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydro-7-methoxyquinoline dihydrochloride (1.0 g) 48% hydrobromic acid (10 ml) was heated under reflux for 4 hr. The reaction mixture was poured into 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (0.81 g). The melting point of its dihydrochloride was 151-152xc2x0 C. (recrystallizing solvent; methanol-diisopropyl ether).
Methyl 4-hydroxyimino-6-methoxytetralin-2-carboxylate (2.909 g, Journal of Medicinal Chemistry, 21, 1105-1110, 1978) was heated with polyphosphoric acid (30.22 g) at 100xc2x0 C. for 1.5 hr and cooled. Ice-water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (2.125 g).
m.p.: 114-116xc2x0 C.
To a solution of methyl 2,3,4,5-tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine-4-carboxylate (5.035 g) in methanol (60 ml) was added 1 N aqueous sodium hydroxide (40 ml). The reaction mixture was stirred at room temperature for 6.5 hr, made acidic by adding 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (4.253 g).
m.p.: 202-204xc2x0 C.
2,3,4,5-Tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine-4-carboxylic acid (4.013 g) was heated with 48% hydrobromic acid (40 ml) for 14 hr and cooled. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in methanol (100 ml) and thionyl chloride (1.3 ml) was added to the solution at 0xc2x0 C. After stirring for 3 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The crude crystals were washed with diethyl ether to obtain the titled compound (3.239 g).
m.p.: 174-177xc2x0 C.
A mixture of methyl [1,2,3,4-tetrahydro-7-hydroxy-2-oxo-3-quinoline]acetate (3.025 g), 4-chloromethylbiphenyl (2.864 g), and potassium carbonate (2.137 g) in DMF (80 ml) was stirred at room temperature for 5 days. The reaction mixture was diluted with water and extracted with a combined solvent of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were washed with ethyl acetate-hexane to obtain the titled compound (4.540 g).
m.p.: 174-178xc2x0 C.
To a solution of methyl [7-(4-biphenylyl)methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline ]acetate (2.475 g) in THF (60 ml) were added methanol (30 ml) and 1 N aqueous sodium hydroxide (12 ml). After stirring at room temperature for 2 days, the reaction mixture was made acidic by adding 1 N aqueous hydrochloric acid and extracted with combined solvent of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The resulting crystals were washed with diisopropyl ether to obtain the titled compound (1.895 g).
m.p.: 193-206xc2x0 C. (decomposed).
A mixture of [7-(4-biphenylyl)methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline]acetic acid (1.616 g), dimethylamine hydrochloride (0.674 g), 1-hydroxybenzotriazole (0.648 g), WSC (0.980 g), and N-methylmorpholine (2.0 ml) in THF (50 ml) and acetonitrile (50 ml) was stirred at room temperature for 2 days. The reaction mixture was diluted with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride and dried, and concentrated. The crude crystals were washed with diisopropyl ether to obtain the titled compound (1.557 g).
m.p.: 199-202xc2x0 C.
A mixture of (6-hydroxy-1-oxo-2-tetralin)acetic acid (1.672 g, EP140684), dimethylamine hydrochloride (0.754 g), 1-hydroxybenzotriazole (1.468 g), and WSC (2.255 g), and triethylamine (3.1 ml) in THF (30 ml) and acetonitrile (30 ml) was stirred at room temperature for 36 hr. The reaction mixture was diluted with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried, and concentrated. The crude crystals were recrystallized from methanol-diisopropyl ether to obtain the titled compound (0.744 g).
m.p.: 181-186xc2x0 C.
To a solution of N,N-dimethyl-(6-hydroxy-1-oxo-2-tetralin) acetamide (0.313 g), 4-chloromethylbiphenyl (0.300g) in DMF (5 ml) was added sodium hydride (60% in oil, 80 mg) and the reaction mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1). The resulting crystals were washed with diisopropyl ether to obtain the titled compound (0.200 g).
m.p.: 131-135xc2x0 C.
To a solution of [6-(4-biphenylyl)methoxy-1-oxo-2-tetralin]-N,N-dimethylacetamide (0.954 g) in ethyl acetate (20 ml) and methanol (20 ml) was added sodium borohydride (0.175 g) at room temperature. After stirring at room temperature for 30 min, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in toluene (30 ml) and heated under reflux in the presence of pyridinium p-toluenesulfonate (0.030 g) for 1.5 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried, and concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (0.779 g).
m.p.: 125-130xc2x0 C.
The titled compound was synthesized using similar method as in Example 38.
m.p.: 145-146xc2x0 C. (recrystallizing solvent; ethyl acetate-hexane).
6-(4-Biphenylyl)methoxy-2-[2-(N,N-dimethylamino) ethyl]tetralin hydrochloride (1.269 g) was converted into its free form and dissolved in acetone (15 ml). 70% m-Chloroperbenzoic acid (0.777 g) was added to the solution at 0xc2x0 C. The reaction mixture was stirred at 0xc2x0 C. for 25 min and precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diethyl ether successively and recrystallized from THF-ethyl acetate to obtain the titled compound (0.811 g).
m.p.: 125-128xc2x0 C.
6-(4-Biphenylyl)methoxy-2-[2-(N,N-diethylamino) ethyl]tetralin hydrochloride (134 mg) was converted into its free form and dissolved in acetone (5 ml). 70% m-Chloroperbenzoic acid (83 mg) was added to the solution at 0xc2x0 C. The reaction mixture was stirred at 0xc2x0 C. for one hr and diluted with 1 N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The crude product was recrystallized from ethyl acetate-hexane to obtain the titled compound (120 mg).
m.p.: 99-104xc2x0 C.
To a solution of (+)-2-[2-(N,N-dimethylamino) ethyl]-6-hydroxytetralin (0.220 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.049 g) at room temperature. The reaction mixture was stirred at 50xc2x0 C. for 30 min. To the reaction mixture, cooled at 0xc2x0 C., was added a solution of 2-bromo-5-pyridylmethylbromide (0.462g) in THF (5 ml). After stirring at 0xc2x0 C. for 2 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:4) and converted into its dihydrochloride, which was recrystallized from ethanol-ethyl acetate to obtain the titled compound (295 mg).
m.p.: 171-181xc2x0 C. (decomposed).
[xcex1]D20=+41.2xc2x0 (c=0.500 in methanol).
6-Amino-2-(N,N-dimethylamino)methyltetralin (0.216 g; obtained in Reference Example 32) was dissolved in pyridine (10 ml), to which was added 4-biphenylcarbonyl chloride (0.311 g). The reaction mixture was stirred at room temperature for 12 hours, pyridine was evaporated out under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/1), and then processed with 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-ethyl acetate to obtain the entitled compound (0.224 g).
m.p.:  greater than 250xc2x0 C.
1H NMR xcex4: 1.24-1.54(1H,m), 1.84-2.10(2H,m), 2.20-2.50(3H,m), 2.26(6H,s), 2.79-3.01(3H,m), 7.10(1H,d,J=8 Hz), 7.28-7.54(5H,m), 7.60-7.82(5H,m), 7.94(2H,d,J=8 Hz).
IR (KBr): 3028, 2910, 2640, 1658, 1538, 1417, 746, 701 cmxe2x88x921.